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At the heart of programming: the role of micro-RNAs

Part of: DOHaD on International Women's Day 2020 French DOHaD

Published online by Cambridge University Press:  18 June 2018

B. Siddeek ,
C. Mauduit ,
C. Yzydorczyk ,
M. Benahmed  and
U. Simeoni
B. Siddeek*
Affiliation:
Woman-Mother-Child-Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
C. Mauduit
Affiliation:
INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice, France
C. Yzydorczyk
Affiliation:
Woman-Mother-Child-Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
M. Benahmed
Affiliation:
INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice, France
U. Simeoni
Affiliation:
Woman-Mother-Child-Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
*
Address for correspondence: Benazir Siddeek, Woman-Mother-Child-Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland. E-mail: Benazir.Siddeek@chuv.ch
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Abstract

Epidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an ‘altered programming’ of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health. In particular, micro-RNAs which are involved in each step of heart development and functions seem to play a crucial role in the unfavorable programming of heart diseases. This review describes the latest advances in micro-RNA research in heart diseases driven by early exposure to challenges and discusses the use of micro-RNAs as potential targets in the reversal of the pathophysiology.

Keywords

cardio-metabolic dysfunctionsmicro-RNAsprogrammingreversal

Information

Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 9 , Issue 6 , December 2018 , pp. 615 - 631
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018 

Origins of heart diseases

The heart is the first organ to form during embryogenesis.Reference Marín-García 1 Its development is a highly regulated process relying on the intervention of various factors that orchestrate cardiac morphogenesis, myogenesis, contractility and metabolism. Mammalian heart undergoes considerable maturation in utero, such that the majority of cardiomyocytes, present shortly after birth, beat for a lifetime.Reference Thornburg, Jonker and O’Tierney 2 , Reference Van Berlo and Molkentin 3 Thus, an early challenge altering cardiomyocytes maturation, endowment and growth in utero can give rise to coronary artery disease,Reference Bubb, Cock and Black 4 cardiomyopathy,Reference Nakano, Minami and Braas 5 myocarditis,Reference Buyon, Swersky, Fox, Bierman and Winchester 6 congenital malformationsReference Cole, Yutzey and Brar 7 and valvular disease,Reference Mills, Troendle, Conley, Carter and Druschel 8 which can impact lifelong cardiac functions and lead to heart failure. By affecting at least 26 million people,Reference Savarese and Lund 9 heart failure is a worldwide leading cause of death. Heart failure corresponds to the incapacity of the heart to maintain an adequate circulation of blood in the bodily tissues. Heart failure can be caused by inherited disorders or develop after birth, and the reason behind this remains, most of the time, unknown. Mutations in a variety of genes have been associated with heart diseases in human.Reference Ghouse, Skov, Bigseth, Ahlberg, Kanters and Olesen 10 , Reference Nolte, Munoz and Tragante 11 In addition, the use of animal models based on gene mutations suggests a multiplicity of pathways affecting cardiomyocytes such as transcriptional control,Reference Lin, Schwarz, Bucana and Olson 12 calcium homeostasis,Reference Tzimas, Johnson and Santiago 13 force generation and transmission,Reference Ruggiero, Chen, Lombardi, Rodriguez and Marian 14 as well as metabolism.Reference Slingo, Cole and Carr 15 The use of fast and cost-effective technologies, genetic testing based on the entire exome or genome sequencingReference Crotti, Johnson and Graf 16 revealed a high number of variants which have little effect on cardiac health conditions. A number of polymorphisms have been suggested as a risk factor for heart diseases, however, most of these variants represent susceptibilities that require additional mutations or injury to cause the phenotype of disease. As such, polymorphisms in the adrenergic pathway,Reference Dorn, Triposkiadis, Karayannis, Giamouzis, Skoularigis, Louridas and Butler 17 G protein-coupled receptor kinases,Reference Liggett, Cresci and Kelly 18 in the renin–angiotensin–aldosterone systemReference Danser, Schalekamp and Bax 19 , Reference Bai, Wang, Hu and Wei 20 have been described.

Besides genetic causes of heart failure, environment,Reference Humblet, Birnbaum, Rimm, Mittleman and Hauser 21 – Reference Pan, Li and Tsai 24 nutrition and lifestyleReference Pharr, Coughenour and Bungum 25 – Reference Iribarren, Tekawa, Sidney and Friedman 27 have a major impact on heart function. Diet, obesity, diabetes and alcohol consumption (in a dose-dependent mannerReference Catena, Colussi and Verheyen 28 – Reference Brunner, Herbel and Drobesch 30 ) are particularly of high concern in heart disease etiology. Given the worldwide epidemic of obesity and metabolic disorders, strong efforts are being made to gain insight into the mechanisms of cardiovascular health influenced by nutrition. The important role of nutrition on cardiac functions is reflected by the model of mice fed through their long-term feeding with high-fat diet which results in cardiac hypertrophy and fibrosisReference Wang, Li, Zhao, Peng and Zuo 31 – Reference Bobbert, Jenke and Bobbert 33 associated with lipotoxicity.Reference Christoffersen, Bollano and Lindegaard 34 Interestingly enough, correlations between myocardial lipid accumulation and cardiac dysfunction have been noted in humans. When comparing healthy lean individuals to individuals with moderate obesity, an increase in triglyceride accumulation precedes ventricular hypertrophy.Reference Kankaanpaa, Lehto and Parkka 35 Experience of stress such as long-term stress (i.e. work related) as well as acute stress (e.g. experienced during an earthquake,Reference Trichopoulos, Katsouyanni, Zavitsanos, Tzonou and Dalla-Vorgia 36 a terrorist attackReference Kark, Goldman and Epstein 37 or an industrial accidentReference Ruidavets, Paterniti, Bongard, Giroux, Cassadou and Ferrieres 38 ) triggers coronary heart disease,Reference Chandola, Britton and Brunner 39 myocardial infarction or stroke. Those factors linked to environment, nutrition and lifestyle have stronger effects on heart when they occur early during development.

Early exposure to environmental challenges induces cardiac disorders

Since the work of Professor D.J. Barker and the hypothesis of the Developmental Origins of Health and Disease (DOHaD) providing a framework to assess the effect of early nutrition and growth on long-term health, a bulk of data identified the developmental period as a phase when the fetus integrate information from the fetal milieu allowing the organism to adapt to change later in life. The fetus learns to adapt to the environment it expects to encounter once outside of the womb. Such ‘programming’ is a normal, adaptive component of development by which the fetus is predisposed to inhabit an environment with expected resources. When fetal conditions do not match the environment later during life, the child or the adult can develop non-adapted physiological response to the environment. As such, a challenge during fetal life can therefore modify the developmental trajectory and change the developmental ‘predictive adaptive’ response to the adverse in utero environment into maladaptive in adulthood if conditions (e.g. diet and lifestyle) change. Given that turnover of human cardiomyocytes is limited over a lifetime, the heart is particularly sensitive to challenges that perturb the intrauterine environment. In addition to acute effects that may drive long-lasting cardiac dysfunction,Reference Auger, Fraser, Sauve, Bilodeau-Bertrand and Kosatsky 40 early developmental exposure to environmental challenges can induce changes that may impact cardiac functions only later in life (Fig. 1). Insults during infancy, gestational and periconceptional periods are associated with an increased risk of heart diseases in offspring. Fetal hypoxia is one of the most common consequences of complicated pregnancies, occurring during preeclampsia, placental insufficiency or infection. In sheep, a large animal model in which the timing of cardiomyocyte maturation is similar to human, prenatal hypoxia can promote fetal growth restriction associated with a reduction in the total number of cardiomyocyte.Reference Brain, Allison and Niu 41 In perturbed intrauterine environments such as fetal hypoxia,Reference Giussani, Camm and Niu 42 placental insufficiency and malnutrition,Reference Forsen, Eriksson, Tuomilehto, Teramo, Osmond and Barker 43 , Reference Roseboom, De Rooij and Painter 44 adaptations made by the fetus cause permanent changes in tissue structure and function, with depressed cardiac performance and cardiomyopathies that persist into adulthood.Reference Tintu, Rouwet and Verlohren 45 , Reference Botting, McMillen, Forbes, Nyengaard and Morrison 46 Those defects have been associated with left ventricular hypertrophy, altered myocardial contractility, endothelial dysfunction,Reference Brain, Allison and Niu 41 susceptibility to ischemia reperfusion injuryReference Rueda-Clausen, Morton, Lopaschuk and Davidge 47 and premature cardiac ageing phenotype.Reference Kuo, Li, Li, Huber, Nathanielsz and Clarke 48 Several underlying mechanisms have been proposed, including an increase in beta(2)-adrenoreceptor and the G(s)alpha/G(i)alpha ratio, and a decrease in heat shock protein 70 and endothelial nitric oxide synthase in the left ventricle,Reference Li, Xiao, Estrella, Ducsay, Gilbert and Zhang 49 or increased expression of insulin-like growth factor 2 (IGF-2) and its receptor IGF-2R in utero growth,Reference Wang, Zhang and McMillen 50 as well as up-regulated IGF-2R-Gαq signaling in low-birthweight lamb.Reference Wang, Tosh and Zhang 51 In the context of exposure to nutritional excess during perinatal life such as maternal obesity and hyperglycemiaReference Lin, Yang, Reece and Yang 52 as well as child obesity, impaired cardiac function,Reference Martins, Vieira, de Souza and Moura 53 are induced later in life. These exposures change the programming of cardiac metabolism, inducing excessive lipid accumulation in myocardial cellsReference Borradaile and Schaffer 54 , Reference Christoffersen, Bollano and Lindegaard 34 and defects in cardiac insulin signaling.Reference Martins, Vieira, de Souza and Moura 53

Fig. 1

Lifelong environmental challenges that alter heart functions. Numbers indicate the references of studies associating environmental challenges and cardiac alterations. ART, assisted reproductive technologies.

In the early origin of cardiac dysfunctions, the existence of sensitive developmental windows of exposure had been only addressed in a few studies which highlighted the impact levels according to the time of exposure. In the case of high-fat diet, adult cardiac alterations including increased heart rate were described when the exposure occurred after weaning.Reference Fiorino, Americo and Muller 55 Another study which compared in utero and post-weaning period of exposure to a high-fat high-sugar diet showed that exposure in the post-weaning period has a more profound effect on offspring weight gain and glucose tolerance than maternal overnutrition.Reference King, Norman, Seckl and Drake 56 The analyses of metabolic alterations suggest that post-weaning period is critical in the altered programming of offspring health by nutrition. These data emphasize the importance of optimizing early life nutrition in offspring of both obese and lean mothers. However, the effects of those exposures were studied on rodent where postnatal period correspond developmentally to the late gestation period in human. The critical developmental window of exposure thus, remains to be investigated in human. In the case of caffeine, mice exposed in utero to an equivalent to two to four cups of coffee at an early embryonic stage, develop a greater risk of dilated cardiomyopathy in adulthood. When the exposure occurs at a later embryonic stage, that is to say when germ cells develop, inter-generational (in F2 and F3) hypertrophic cardiomyopathy is induced.Reference Fang, Poulsen, Rivkees and Wendler 57 During this critical developmental period, the high sensitivity of the heart to toxicants is observed in the response to low doses of the toxicant. Indeed, some factors can have no impact at a determined dose level in adulthood whereas it can trigger profound effects when the exposure occurs early in life, such as alcohol. While in adulthood the effects of alcohol consumption on cardiac health depends on the dose, during pregnancy, even relatively low doses of alcohol consumed can be detrimental to long-term cardiac health in the offspring by inducing ventricular hypertrophy and fibrosis in adulthood.Reference Nguyen, Probyn and Campbell 58 Despite public health warnings, younger women continue to smoke during pregnancy.Reference Reitan and Callinan 59 Gestational exposure to nicotine induces higher risk of perinatalReference Butler, Goldstein and Ross 60 and obstetric complications.Reference Coste, Job-Spira and Fernandez 61 Fetal exposure to nicotine induces alteration in the cardiac conduction system with disrupted heart rate and electrical conductionReference Ton, Biet, Delabre, Morin and Dumaine 62 which has been suggested as an underlying mechanism for sudden death. A number of studies showed that fetal heart is sensitive to maternal stress.Reference Makino, Matsuda and Yoneyama 63 Stress experienced postnatally, during maternal separation, increases risk of heart diseases in animalsReference Sanders and Anticevic 64 (e.g. increased heart rate response) and humansReference Alastalo, Raikkonen and Pesonen 65 (e.g. increased risk of developing coronary heart disease) as observed in children born in Helsinki between 1934 and 1944 and who were separated from their parents. The developing cardiovascular system is a sensitive target of many environmental pollutants, including dioxins,Reference Aragon, Kopf, Campen, Huwe and Walker 66 , Reference Thackaberry, Nunez, Ivnitski-Steele, Friggins and Walker 67 and a plasticizer, the Bisphenol A (BPA)Reference Chapalamadugu, Vandevoort, Settles, Robison and Murdoch 68 which induce long-term alterations in offspring heart such as hypertrophy. Furthermore, when associated with a second hit during life (like unbalanced diet), prenatal exposure to toxicant has been shown to produce a more pronounced phenotype in adulthood. For example, when coupled with postnatal overfeeding, BPA treatment produced a stronger phenotype with significant increase in inter-ventricular septal thickness indicating that BPA pre-treatment alters the trajectory of cardiac function differentially from overfeeding alone that may be adaptive v. maladaptive.Reference MohanKumar, Rajendran and Vyas 69

Assisted reproductive technologies (ARTs) are widely used in infertility treatment. Emerging evidence indicates that ART is a risk factor for heart diseases in offspring.Reference Valenzuela-Alcaraz, Crispi and Bijnens 70 , Reference Scherrer, Rexhaj, Allemann, Sartori and Rimoldi 71 Hypotheses attribute the effect of ART on cardiovascular health to embryo manipulation in suboptimal culture conditions or ART-related fetal insults, or other parental factors. For instance, the advanced parental age was suggested to be a risk factor of heart malformation in the offspring.Reference Materna-Kiryluk, Wisniewska and Badura-Stronka 72 , Reference Su, Yuan, Huang, Olsen and Li 73 Strikingly, parental exposures not only influences cardiac health at an inter-generational level, but also at a trans-generational level.Reference Keverne 74 While mother contribution is well described through the transmission of biomolecules (nutrients or hormones), environmental influences (temperature) or behavior (anxiety) to their offspring, the paternal contribution has been for a long time not considered and under debate. Recently, increasing evidence is pointing out the role of paternal contribution to offspring health.Reference Hughes 75 For example, the Overkalix cohort study (in Sweden) showed that men who had experienced famine before puberty were less likely to have grandsons with cardiovascular disease than men who had plenty to eat.Reference Kaati, Bygren and Edvinsson 76 In inter- and trans-generational transmission of acquired traits, epigenetic marks have been highlighted as underlying molecular bases. The discovery of epigenetic mechanisms including micro-RNAsReference Bartel 77 that induce specific phenotypes without change in DNA sequence improved our understanding of DOHaD field while for many years the early developmental period was considered to be controlled by the genetic program. Indeed, a single genome gives rise in development to over 100 different types of cells. The same genome is present in all of these cells but their functions are remarkably different. This is achieved through different epigenetic programming in each of these cell types. As such, the early epigenome adds powerful layers of diversity to the biologic predisposition generated by the genome.

Micro-RNAs in heart development and diseases

Heart development is orchestrated by epigenetic processes. The major epigenetic features include DNA methylation, post-translational histone modifications and non-coding RNAs, including small non-coding RNAs (e.g. piRNAs and micro-RNAs). In close interaction with DNA methylation and histone post-translational modifications, non-coding RNAs regulate gene expression. These mechanisms regulate the critical steps of heart development involving coordinated cellular proliferation, migration, differentiation and programmed cell death, structural remodeling,Reference Martinez, Gay and Zhang 78 and the control of metabolic homeostasis through the regulation of glucose and lipid metabolism, and insulin signaling.Reference Sandovici, Smith and Nitert 79 Recent studies have revealed important roles for micro-RNAs in heart developmentReference Yan and Jiao 80 and diseaseReference Latronico and Condorelli 81 – Reference Trajkovski, Hausser and Soutschek 83 (Table 1).

Table 1

Micro-RNAs associated to cardiac pathophysiology

HF: heart failure, ARRH: arrhythmia, CAD: coronary artery disease, CHD: congenital heart disease, VALV: valvular disease, FIBRO: fibrosis, HYPER: hypertrophy, MI: myocardial infarction, DIA: diabetic heart disease, MC: myocarditis.

Non exhaustive list of micro-RNAs that have been described in animal and/or human models of cardiac diseases. Orange color squares indicates micro-RNAs that were reported in specific cardiac disease. The reference of the study highlighting the involvement of micro-RNA in specific cardiac disease is indicated in each orange square.

Micro-RNA biogenesis and mode of action

While only 1–2% of the genome encode for proteins, the main part gives rise to non-coding RNAs (ncRNAs) including micro-RNAs. Micro-RNAs originate from sequences disseminated throughout the genome, from introns or intergenic regions. Mature micro-RNAs are small nucleotide sequences (19–24 nucleotides in length). Some micro-RNAs are involved in pathways that are conserved throughout phylogeny while micro-RNA diversity correlates with speciation. The number of micro-RNA and targets of micro-RNAs reveals morphological complexities observed in animals.Reference Lee, Risom and Strauss 84 Importantly, given that ~60% of the human genes are under their control, micro-RNAs are master regulators at the post-transcriptional levelReference Friedman, Farh, Burge and Bartel 85 and play important roles in many biological processes, including development, differentiation, proliferation, apoptosis, metabolism and tissue remodeling.

Micro-RNA biogenesis is based on a series of steps that go from transcription of primary micro-RNAs (pri-micro-RNAs) to the biologically active, mature micro-RNAs (Fig. 2). First, DNA sequences are transcribed into pri-micro-RNAs mainly through the action of RNA polymerase II,Reference Lee, Kim and Han 86 and to a less extent by RNA Polymerase III.Reference Borchert, Lanier and Davidson 87 The transcribed pri-micro-RNAs are then cleaved by DROSHA and its cofactor DiGeorge critical region 8 (DGCR8) in the nucleus generating micro-RNA precursors about 60–70 nt called pre-micro-RNAs.Reference Han, Lee, Yeom, Kim, Jin and Kim 88 These pre-micro-RNAs shuttle into the cytoplasm by interacting with the nuclear pore complex Exportin-5.Reference Yi, Qin, Macara and Cullen 89 Once in the cytoplasm, the hairpin structures, known as pre-micro-RNAs, undergo further processing by the DICER–TAR RNA-binding protein 2 (TRBP) complex to produce fully processed RNA duplexes (around 22 nucleotides in length) comprising the mature micro-RNAs and the micro-RNAs* (also known as passenger strands).Reference Wilson, Tambe, Kidwell, Noland, Schneider and Doudna 90 Each micro-RNA strand is incorporated into an RNA-induced silencing complex (RISC) comprising an Argonaute (AGO) protein that binds to the target mRNA and degrades the passenger strand.Reference Maniataki and Mourelatos 91 The mature micro-RNA guides the RISC to target sequences located mainly in the 3’UTR of the target messenger RNA leading to an inhibition of its translation or to its degradation. In addition to their classical roles, micro-RNAs regulate gene expression through promoter targeting and translational activation.Reference Place, Li, Pookot, Noonan and Dahiya 92 , Reference Bruno, Karam and Huang 93 Binding to the 5’UTR and to exon sequence have also been described.Reference Atambayeva, Niyazova and Ivashchenko 94 Interestingly, the micro-RNA biogenesis machinery is regulated by hypoxia, hormonal and dietary changes.Reference Davis and Ross 95 – Reference Kulshreshtha, Ferracin, Negrini, Calin, Davuluri and Ivan 97 More recently, extracellular, circulating micro-RNAs have been described as highly stable, and as potential blood-based biomarkers for diseases,Reference Siddeek, Inoubli and Lakhdari 98 including heart diseases. We will focus this review on the involvement of micro-RNAs in heart health and disease and especially their involvement in heart disease programming.

Fig. 2

Micro-RNAs biogenesis. Micro-RNAs biogenesis involves different steps. Pri-micro-RNAs are transcribed from inter- and intra-genic regions. They are then processed into pre-micro-RNAs and double-stranded micro-RNAs. The mature single-stranded micro-RNAs binds to the UTR ends of targets messenger RNAs (mRNAs) to regulate their levels.

Micro-RNAs regulate cardiac development and function

Advances in micro-RNA analysis such as next generation high depth sequencing techniques have highlighted their critical role in heart functions. As revealed by conditional knock out of Dicer in cardiac tissue, defects in micro-RNA biogenesis affect both embryonic development and postnatal cardiac maintenance and function.Reference da Costa Martins, Bourajjaj and Gladka 99 – Reference Bernstein, Kim and Carmell 102 One important role of micro-RNAs in heart development and function is linked to their ability to regulate the cardiac transcriptional pathways that maintain a restricted and specific pattern of gene expression.Reference Wang 103 Experimental studies on animals and analyses of human samples address specific roles of different micro-RNAs.

Several clinical and experimental studies have described the importance of dysregulation of micro-RNAs in the origin of cardiac disorders (Table 1), such as coronary artery disease,Reference Rottiers and Naar 104 cardiac fibrosis and hypertrophy.Reference Yang, Li and Wang 105 Among them, a few micro-RNAs, including miR-1, miR-133, miR-208 and miR-499 which regulate cell proliferation, differentiation and apoptosis in cardiac tissue from the early developmental stages, have been described as key players in heart disease development. Their alterations have been reported in cardiac hypertrophy, myocardial infarction, cardiac arrhythmia and heart failure.Reference Wang and Cai 106 MiR-1, the first micro-RNA that has been implicated in heart development, exerts its action through the targeting of multiple pathways. For instance, miR-1 negatively regulates proliferation and mediates cell cycle withdrawal by targeting heart and neural crest derivatives expressed 2 (HAND2),Reference Zhao, Samal and Srivastava 107 cell division cycle 42 (CDC42)Reference Qian, Wythe and Liu 108 and the serine/threonine kinase PIM-1.Reference Chen, Yin and Jiang 109 MiR-1 levels are also key player in cardiomyocyte differentiation and cell fate decision by down-regulating Notch ligand delta 1 (DLL1).Reference Kwon, Han, Olson and Srivastava 110 In addition, miR-1 regulates contractility of cardiomyocyte by controlling calcium homeostasisReference Ali, Huang and Maher 111 and electrical conduction.Reference Zhao, Ransom and Li 112 Indeed, it down-regulates Iroquois Homeobox 4 and 5, IRX4 and IRX5 which are involved in the regulation of the cardiac repolarisation gradientReference Besser, Malan and Wystub 113 and genes that are involved in gap junction and iron channel such as GJA1,Reference Curcio, Torella and Iaconetti 114 or the cardiac L-type calcium channel gene CACNA1C (CAV1.2).Reference Rau, Freyermuth and Fugier 115 MiR-1 has also displayed its important role in diabetic cardiac dysfunction. In a mouse model of streptozotocin-induced diabetes, miR-1 down-regulation may be involved in the development of cardiac hypertrophy.Reference Costantino, Paneni, Luscher and Cosentino 116 qA study performed on diabetic patients’ cohorts highlights the potential of serum miR-1 as a biomarker of myocardial steatosis.Reference De Gonzalo-Calvo, Van der Meer and Rijzewijk 117

Furthermore, micro-RNAs have been highlighted as sensitive biomarkers of cardiac dysfunction and prognostic markers for diseases. Indeed, changes in their profile in diabetic individuals with normal ejection fraction are detected before clinical manifestations of heart diseases,Reference Rawal, Ram and Coffey 118 , Reference Zampetaki, Kiechl and Drozdov 119 and are dynamic in response to therapeutic treatment (i.e. diabetic cardiac microangiopathy).Reference Flowers, Aouizerat and Abbasi 120 Just as gene polymorphism, micro-RNAs polymorphism can represent risk for heart diseases. For instance, meta-analyses performed on a total of 13 related studies involving 8120 patients and 8364 controls suggest that polymorphism in miR-146a (rs2910164), microR-196a2 (rs11614913) and miR-499 (rs3746444) are associated with coronary heart disease risk.Reference Liu, You, Zhou and Zhang 121

Micro-RNAs at the origins of cardiac disorders induced by environment, lifestyle and diet

Deregulation of micro-RNAs profile has been suggested as a potential mechanism at the origin of heart diseases induced by environment and lifestyle.Reference Lock, Botting, Tellam, Brooks and Morrison 122 In cardiac alterations induced by fetal hypoxia, a few micro-RNAs have been identified. Among these, miR-210 was highlighted at the origin of fetal rat cardiomyocytes death induced by hypoxia through the suppression of glucocorticoid receptor (NR3C1).Reference Martinez, Ma, Dasgupta, Meng and Zhang 123 MiR-210 is regulated by the binding of hypoxia-inducible factor 1-alpha (HIF-1-α) to its promoter, and due to its consistent and powerful response to hypoxia, miR-210 is termed as the master micro-RNA regulating the cellular response to hypoxia.Reference Chan, Banerjee, Choi and Sen 124 , Reference Huang and Zuo 125 Besides miR-210, other micro-RNAs such as miR-2285, miR-34, miR-192, miR-449, miR-200 families and miR-199a-214 cluster, have been associated with hypoxia, for example in high-altitude adaptationReference Guan, Long and Ma 126 or in pathological condition.Reference El Azzouzi, Leptidis and Dirkx 127 Changes in micro-RNA profile have been proposed as underlying mechanisms in the cardiac alterations driven by maternal exposure to dietary challenges, through the deregulation of cell death, growth and proliferation in the fetal heart.Reference Maloyan, Muralimanoharan and Huffman 128 In animals exposed to high-fat diet, a number of pathways altering cardiomyocyte metabolism have been described. For instance, mice exposed to high-fat diet exhibit cardiac lipotoxicity through the dysregulation of a major cellular sensor of energy availability, AMP-activated protein kinase (AMPK), and its upstream regulators, the calcium-binding protein 39 (CAB39) and the liver kinase B1 (LKB1).Reference Kuwabara, Horie and Baba 129 MiR-451 has been shown to regulate this LKB1/AMPK pathway and cardiac lipotoxicity through the targeting of CAB39.Reference Kuwabara, Horie and Baba 129 Similarly, dysregulated glycogen synthase kinase 3 (GSK3B) and glucose transporter 4 (GLUT4), involved in the insulin signaling pathway, have been associated with alterations in miR-29c, miR-21a-3p, miR-29c-3p, miR-144–3p and miR-195a-3p levels in the heart of animals exposed to high-fat diet.Reference Guedes, Franca and Lino 130 Exposure to maternal hyperglycemia, induces cardiovascular dysfunctions in offspring. Evidence suggests that those dysfunction are due to altered levels of enhancer of zeste homolog 2 (EZH2) driven by miR-101 in fetal endothelial cells.Reference Floris, Descamps and Vardeu 131 Interestingly, miR-101 and EZH2 have been highlighted in other models of fetal programming of adult diseases (e.g. infertility) driven by early exposure to endocrine disruptors.Reference Siddeek, Lakhdari and Inoubli 132 Not only in utero exposure affects cardiac micro-RNAs in short term,Reference Maloyan, Muralimanoharan and Huffman 128 but also in long term.Reference Fernandez-Twinn, Blackmore and Siggens 133 As such, in mice, a maternal obesogenic diet during gestation and lactation induces miR-133a alteration in the offspring heart at 8 weeks of age associated with cardiac hypertrophy.Reference Fernandez-Twinn, Blackmore and Siggens 133 Furthermore, as highlighted by a recent study, the impact of in utero exposure to dietary challenges on long-term cardiac function depends on the timing of the exposure during development.Reference Wing-Lun, Eaton and Hur 134 In this study, the comparison between prenatal exposure to maternal obesity and/or postnatal exposure to a Western diet on micro-RNA expression profiles showed that many more cardiac micro-RNA implicated in various cardiac pathologiesReference Wing-Lun, Eaton and Hur 134 are altered in response to a relatively short period of postnatal overnutrition, rather than by a longer period of prenatal overnutrition.Reference Wing-Lun, Eaton and Hur 134 Furthermore, cardiac micro-RNAs not only regulate functions, but also regulate metabolism at the body level. Indeed, miR-208 which cardiac levels are increased in high-fat diet mice, regulates the mediator complex subunit 13 (Med13) involved in the regulation energy balance in the heart.Reference Grueter, Van Rooij and Johnson 135 Cardiac inhibition of miR-208 is sufficient to confer resistance to obesity in high-fat diet mice.Reference Grueter, Van Rooij and Johnson 135 This observation highlights a novel role of cardiac micro-RNA, as a hormone-like controller on whole-body metabolism. In the effects driven by in utero exposure to environmental toxicants (such as BPA) on cardiac remodeling, a study performed in monkeys highlighted the involvement of miR-205 and miR-224.Reference Chapalamadugu, Vandevoort, Settles, Robison and Murdoch 68 The cellular pathways involved have been more detailed in a model of cardiomyocyte cell line exposed to a persistent organic pollutant, the polychlorinated biphenyls (PCBs). As revealed in this in vitro model, the deregulation of micro-RNAs involved in cardiomyocyte differentiation is a potential underlying mechanism in PCB driven cardiac dysfunction.Reference Zhu, Yu and Zhu 136

Micro-RNAs, a target for the reversal of heart disease programming?

Given their key function in gene regulation, micro-RNAs provide promising therapeutic targets.Reference Christopher, Kaur, Kaur, Kaur, Gupta and Bansal 137 Advances in micro-RNA chemistry and delivery technologies allowed the development of powerful tools for in vivo regulation of micro-RNAs.Reference Rupaimoole and Slack 138 In the treatment of post-myocardial infarction, cardiac remodeling and dysfunction, hypertrophy, heart failure, atherosclerosis and myocarditis,Reference Montgomery, Hullinger and Semus 139 , Reference Rayner, Sheedy and Esau 140 animal models of in vivo delivery of micro-RNA mimics or anti-miRs show the potential of micro-RNA based therapy. For instance, the inhibition of micro-RNAs (miR-128,Reference Zeng, Li, Wen and Bi 141 miR-92a,Reference Jiang, Ji and Luo 142 miR-26a,Reference Zhang, Qin and Zhang 143 miR-15Reference Hullinger, Montgomery and Seto 144 or miR-34Reference Bernardo, Gao and Winbanks 145 families) involved in cardiomyocyte cell death induced by myocardial ischemia reduces infarct size after ischemia-reperfusion and augments the recovery of heart function. Pharmacological inhibition of miR-140 which is involved in mitochondrial fission reduces infarct size after acute myocardial infarction in mice.Reference Li, Li and Jiao 146 Inhibition of miR-21Reference Bonci 147 or miR-25Reference Wahlquist, Jeong and Rojas-Munoz 148 prevents heart failure development in mice by restoring cardiac function, reducing fibrosis and normalizing cardiomyocyte cell size. Conversely, micro-RNAs such as miR-210Reference Hu, Huang and Li 149 which protects cardiomyocytes and vasculature, when injected intra intramyocardially, reduce cell death and improve cardiac function and angiogenesis after acute myocardial infarction.Reference Wang, Zhang and Li 150 Research into the role of micro-RNAs in heart disease holds great promise for future therapeutic applications. However, many questions on their delivery and duration of action in human remain. Thus, modification in lifestyle and diet remains the first choice in the micro-RNAs modulation. Interestingly, exercise training improves cardiac autonomic control, cardiac function and arrhythmogenesis in rats with preserved ejection fraction heart failure.Reference Andrade, Arce-Alvarez and Toledo 151 Recently, physical exercise has been shown to modulate cardiac micro-RNAs which are possibly involved in exercise mediate cardioprotection. Modification in these micro-RNAs levels driven by exercise can be detected in the blood, representing potential biomarkers of cardiorespiratory fitness.Reference Denham and Prestes 152 Apoptosis-related micro-RNAs and their downstream proteins in heart can be influenced by swimming training.Reference Zhao and Ma 153 Circulating micro-RNA levels (miR-1, miR-133 and miR-206) are elevated with marathon runningReference Lew, Pearson, Schwenke and Katare 154 and with moderate exercise in pathological conditions like myocardial infarction (miR-1 and miR-214) which are associated with the normalization of Ca2+ handling and left ventricular compliance in infarcted hearts.Reference Melo, Barauna and Neves 155

Recent evidence showed that hydrogen sulfide (H2S) has the potential to protect the heart against diseases.Reference Barr, Shimizu, Lambert, Nicholson and Calvert 156 , Reference Khatua, Adela and Banerjee 157 H2S is a gaseous mediator along with nitric oxide and carbon monoxide, and is produced endogenously from cysteine metabolism in mammalian tissues. Low plasma levels of H2S have been described in type 2 diabetic patients,Reference Jain, Bull and Rains 158 in high-fat diet treated miceReference Peh, Anwar, Ng, Atan, Kumar and Moore 159 and streptozotocin-treated rats.Reference Jain, Bull and Rains 158 Recent evidence showed that H2S has the potential to protect the heart against diseases.Reference Barr, Shimizu, Lambert, Nicholson and Calvert 156 , Reference Khatua, Adela and Banerjee 157 Exogenous H2S treatment mitigates cardiomyopathy induced by diabetes and protects the heart from I/R injury. Interestingly, H2S has been demonstrated to regulate micro-RNAsReference Kesherwani, Nandi, Sharawat, Shahshahan and Mishra 160 in cardiomyocyte cell lines. The preconditioning of myocardial I/R with H2S decreases miR-1-mediated apoptosis.Reference Kang, Hong and Xiao 161 However, in the context of early programming of heart diseases, little is known about the potential of micro-RNAs in the reversal of the pathology. In a rat model of adult cardiac hypertrophy induced by maternal undernutrition, specific cardiac micro-RNA profiles are exhibited and are associated with genes involved in inflammation and cardiovascular development. When the offspring is treated with growth hormone, the cardiac hypertrophy is reversed,Reference Gray, Li, Patel, Reynolds and Vickers 162 accompanied by an up-regulation of cardiac let-7 highlighting the potential of let-7 micro-RNA family in the reversal of cardiac pathophysiology induced by maternal undernutrition. Interestingly, recent study showed that short caloric restriction in adulthood can restore cardiac function in mice that were exposed postnatally to overnutrition.Reference Li, Guenancia and Rigal 163 However, the role of micro-RNAs in the reversal of cardiac alteration programming by nutritional approach remains to be investigated.

Future perspective

How environmental challenges during early life can alter and shape offspring cardiac functions through alterations in micro-RNAs is an intense area of research. However, several questions still need to be elucidated. While evidence exists for the influence of early life insults on micro-RNAs and pathophysiology in adipose tissue, brain, liver and pancreas, evidence for the existence of a causative link between environmental challenges, nutritional constraints, or lifestyle challenges, and micro-RNAs and developmental programming of cardiovascular diseases is still limited. Furthermore, the sensitive developmental windows of exposure and the role of micro-RNAs in gender differences need to be clarified for the different types of challenges. Finally, the targeting of micro-RNAs through nutritional, exercise or pharmacological approaches would provide valuable information that would allow better advice for early prevention, and promote appropriate changes to maximize later life health benefits.

Acknowledgments

The authors acknowledge Suzan Arslan for her valuable help in English editing.

Financial Support

This work was supported by the Centre Hospitalier Universitaire Vaudois (CHUV).

Conflicts of Interest

None.

References

1. Marín-García, J. Post-Genomic Cardiology. 2014. Elsevier Science: Cambridge, MA.Google Scholar
2. Thornburg, K, Jonker, S, O’Tierney, P, et al. Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol. 2011; 106, 289–299.Google Scholar
3. Van Berlo, JH, Molkentin, JD. An emerging consensus on cardiac regeneration. Nat Med. 2014; 20, 1386–1393.Google Scholar
4. Bubb, KJ, Cock, ML, Black, MJ, et al. Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep. J Physiol. 2007; 578, 871–881.Google Scholar
5. Nakano, H, Minami, I, Braas, D, et al. Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. eLife. 2017; 6, e29330.Google Scholar
6. Buyon, JP, Swersky, SH, Fox, HE, Bierman, FZ, Winchester, RJ. Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus. Experience in a mother with a predominance of SS-B (La) antibodies. Arthritis Rheum. 1987; 30, 44–49.Google Scholar
7. Cole, CR, Yutzey, KE, Brar, AK, et al. Congenital heart disease linked to maternal autoimmunity against cardiac myosin. J Immunol. 2014; 192, 4074–4082.Google Scholar
8. Mills, JL, Troendle, J, Conley, MR, Carter, T, Druschel, CM. Maternal obesity and congenital heart defects: a population-based study. Am J Clin Nutr. 2010; 91, 1543–1549.Google Scholar
9. Savarese, G, Lund, LH. Global public health burden of heart failure. Card Fail Rev. 2017; 3, 7–11.Google Scholar
10. Ghouse, J, Skov, MW, Bigseth, RS, Ahlberg, G, Kanters, JK, Olesen, MS. Distinguishing pathogenic mutations from background genetic noise in cardiology: the use of large genome databases for genetic interpretation. Clin Genet. 2018; 93, 459–466.Google Scholar
11. Nolte, IM, Munoz, ML, Tragante, V, et al. Genetic loci associated with heart rate variability and their effects on cardiac disease risk. Nat Commun. 2017; 8, 15805.Google Scholar
12. Lin, Q, Schwarz, J, Bucana, C, Olson, EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science. 1997; 276, 1404–1407.Google Scholar
13. Tzimas, C, Johnson, DM, Santiago, DJ, et al. Impaired calcium homeostasis is associated with sudden cardiac death and arrhythmias in a genetic equivalent mouse model of the human HRC-Ser96Ala variant. Cardiovasc Res. 2017; 113, 1403–1417.Google Scholar
14. Ruggiero, A, Chen, SN, Lombardi, R, Rodriguez, G, Marian, AJ. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc Res. 2013; 97, 44–54.Google Scholar
15. Slingo, M, Cole, M, Carr, C, et al. The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism. Am J Physiol Heart Circ Physiol. 2016; 311, H759–H767.Google Scholar
16. Crotti, L, Johnson, CN, Graf, E, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013; 127, 1009–1017.Google Scholar
17. Dorn, G, Triposkiadis, F, Karayannis, G, Giamouzis, G, Skoularigis, J, Louridas, G, Butler, J. Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol Rev. 2010; 90, 1013–1062.Google Scholar
18. Liggett, SB, Cresci, S, Kelly, RJ, et al. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med. 2008; 14, 510–517.Google Scholar
19. Danser, AH, Schalekamp, MA, Bax, WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995; 92, 1387–1388.Google Scholar
20. Bai, Y, Wang, L, Hu, S, Wei, Y. Association of angiotensin-converting enzyme I/D polymorphism with heart failure: a meta-analysis. Mol Cell Biochem. 2012; 361, 297–304.Google Scholar
21. Humblet, O, Birnbaum, L, Rimm, E, Mittleman, MA, Hauser, R. Dioxins and cardiovascular disease mortality. Environ Health Perspect. 2008; 116, 1443–1448.Google Scholar
22. Yan, S, Song, W, Chen, Y, Hong, K, Rubinstein, J, Wang, HS. Low-dose bisphenol A and estrogen increase ventricular arrhythmias following ischemia-reperfusion in female rat hearts. Food Chem Toxicol. 2013; 56, 75–80.Google Scholar
23. Dzhambov, AM, Dimitrova, DD. Heart disease attributed to occupational noise, vibration and other co-exposure: self-reported population-based survey among Bulgarian workers. Med Pr. 2016; 67, 435–445.Google Scholar
24. Pan, WH, Li, LA, Tsai, MJ. Temperature extremes and mortality from coronary heart disease and cerebral infarction in elderly Chinese. Lancet. 1995; 345, 353–355.Google Scholar
25. Pharr, JR, Coughenour, CA, Bungum, TJ. An assessment of the relationship of physical activity, obesity, and chronic diseases/conditions between active/obese and sedentary/normal weight American women in a national sample. Public Health. 2018; 156, 117–123.Google Scholar
26. Arsenault, BJ, Rana, JS, Lemieux, I, et al. Physical inactivity, abdominal obesity and risk of coronary heart disease in apparently healthy men and women. Int J Obes (Lond). 2010; 34, 340–347.Google Scholar
27. Iribarren, C, Tekawa, IS, Sidney, S, Friedman, GD. Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men. N Engl J Med. 1999; 340, 1773–1780.Google Scholar
28. Catena, C, Colussi, G, Verheyen, ND, et al. Moderate alcohol consumption is associated with left ventricular diastolic dysfunction in nonalcoholic hypertensive patients. Hypertension. 2016; 68, 1208–1216.Google Scholar
29. Park, SK, Moon, K, Ryoo, JH, et al. The association between alcohol consumption and left ventricular diastolic function and geometry change in general Korean population. Eur Heart J Cardiovasc Imaging. 2018; 19, 271–278.Google Scholar
30. Brunner, S, Herbel, R, Drobesch, C, et al. Alcohol consumption, sinus tachycardia, and cardiac arrhythmias at the Munich Octoberfest: results from the Munich Beer Related Electrocardiogram Workup Study (MunichBREW). Eur Heart J. 2017; 38, 2100–2106.Google Scholar
31. Wang, Z, Li, L, Zhao, H, Peng, S, Zuo, Z. Chronic high fat diet induces cardiac hypertrophy and fibrosis in mice. Metabolism. 2015; 64, 917–925.Google Scholar
32. Hall, ME, Harmancey, R, Stec, DE. Lean heart: role of leptin in cardiac hypertrophy and metabolism. World J Cardiol. 2015; 7, 511–524.Google Scholar
33. Bobbert, P, Jenke, A, Bobbert, T, et al. High leptin and resistin expression in chronic heart failure: adverse outcome in patients with dilated and inflammatory cardiomyopathy. Eur J Heart Fail. 2012; 14, 1265–1275.Google Scholar
34. Christoffersen, C, Bollano, E, Lindegaard, ML, et al. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology. 2003; 144, 3483–3490.Google Scholar
35. Kankaanpaa, M, Lehto, HR, Parkka, JP, et al. Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab. 2006; 91, 4689–4695.Google Scholar
36. Trichopoulos, D, Katsouyanni, K, Zavitsanos, X, Tzonou, A, Dalla-Vorgia, P. Psychological stress and fatal heart attack: the Athens (1981) earthquake natural experiment. Lancet. 1983; 1, 441–444.Google Scholar
37. Kark, JD, Goldman, S, Epstein, L. Iraqi missile attacks on Israel. The association of mortality with a life-threatening stressor. JAMA. 1995; 273, 1208–1210.Google Scholar
38. Ruidavets, JB, Paterniti, S, Bongard, V, Giroux, M, Cassadou, S, Ferrieres, J. Triggering of acute coronary syndromes after a chemical plant explosion. Heart. 2006; 92, 257–258.Google Scholar
39. Chandola, T, Britton, A, Brunner, E, et al. Work stress and coronary heart disease: what are the mechanisms? Eur Heart J. 2008; 29, 640–648.Google Scholar
40. Auger, N, Fraser, WD, Sauve, R, Bilodeau-Bertrand, M, Kosatsky, T. Risk of congenital heart defects after ambient heat exposure early in pregnancy. Environ Health Perspect. 2017; 125, 8–14.Google Scholar
41. Brain, KL, Allison, BJ, Niu, Y, et al. Induction of controlled hypoxic pregnancy in large mammalian species. Physiol Rep. 2015; 3, e12614.Google Scholar
42. Giussani, DA, Camm, EJ, Niu, Y, et al. Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress. PLoS One. 2012; 7, e31017.Google Scholar
43. Forsen, T, Eriksson, JG, Tuomilehto, J, Teramo, K, Osmond, C, Barker, DJ. Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ. 1997; 315, 837–840.Google Scholar
44. Roseboom, T, De Rooij, S, Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006; 82, 485–491.Google Scholar
45. Tintu, A, Rouwet, E, Verlohren, S, et al. Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences. PLoS One. 2009; 4, e5155.Google Scholar
46. Botting, KJ, McMillen, IC, Forbes, H, Nyengaard, JR, Morrison, JL. Chronic hypoxemia in late gestation decreases cardiomyocyte number but does not change expression of hypoxia-responsive genes. J Am Heart Assoc. 2014; 3, e000531.Google Scholar
47. Rueda-Clausen, CF, Morton, JS, Lopaschuk, GD, Davidge, ST. Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion. Cardiovasc Res. 2011; 90, 285–294.Google Scholar
48. Kuo, AH, Li, C, Li, J, Huber, HF, Nathanielsz, PW, Clarke, GD. Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing. J Physiol. 2017; 595, 1093–1110.Google Scholar
49. Li, G, Xiao, Y, Estrella, JL, Ducsay, CA, Gilbert, RD, Zhang, L. Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat. J Soc Gynecol Investig. 2003; 10, 265–274.Google Scholar
50. Wang, KC, Zhang, L, McMillen, IC, et al. Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb. J Physiol. 2011; 589, 4709–4722.Google Scholar
51. Wang, KC, Tosh, DN, Zhang, S, et al. IGF-2R-Galphaq signaling and cardiac hypertrophy in the low-birth-weight lamb. Am J Physiol Regul Integr Comp Physiol. 2015; 308, R627–R635.Google Scholar
52. Lin, X, Yang, P, Reece, EA, Yang, P. Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis. Am J Obstet Gynecol. 2017; 217, 216.e1–216.e13.Google Scholar
53. Martins, MR, Vieira, AK, de Souza, EP, Moura, AS. Early overnutrition impairs insulin signaling in the heart of adult Swiss mice. J Endocrinol. 2008; 198, 591–598.Google Scholar
54. Borradaile, NM, Schaffer, JE. Lipotoxicity in the heart. Curr Hypertens Rep. 2005; 7, 412–417.Google Scholar
55. Fiorino, P, Americo, AL, Muller, CR, et al. Exposure to high-fat diet since post-weaning induces cardiometabolic damage in adult rats. Life Sci. 2016; 160, 12–17.Google Scholar
56. King, V, Norman, JE, Seckl, JR, Drake, AJ. Post-weaning diet determines metabolic risk in mice exposed to overnutrition in early life. Reprod Biol Endocrinol. 2014; 12, 73.Google Scholar
57. Fang, X, Poulsen, RR, Rivkees, SA, Wendler, CC. In utero caffeine exposure induces transgenerational effects on the adult heart. Sci Rep. 2016; 6, 34106.Google Scholar
58. Nguyen, VB, Probyn, ME, Campbell, F, et al. Low-dose maternal alcohol consumption: effects in the hearts of offspring in early life and adulthood. Physiol Rep. 2014; 2, e12087.Google Scholar
59. Reitan, T, Callinan, S. Changes in smoking rates among pregnant women and the general female population in Australia, Finland, Norway, and Sweden. Nicotine Tob Res. 2017; 19, 282–289.Google Scholar
60. Butler, NR, Goldstein, H, Ross, EM. Cigarette smoking in pregnancy: its influence on birth weight and perinatal mortality. Br Med J. 1972; 2, 127–130.Google Scholar
61. Coste, J, Job-Spira, N, Fernandez, H. Increased risk of ectopic pregnancy with maternal cigarette smoking. Am J Public Health. 1991; 81, 199–201.Google Scholar
62. Ton, AT, Biet, M, Delabre, JF, Morin, N, Dumaine, R. In-utero exposure to nicotine alters the development of the rabbit cardiac conduction system and provides a potential mechanism for sudden infant death syndrome. Arch Toxicol. 2017; 91, 3947–3960.Google Scholar
63. Makino, I, Matsuda, Y, Yoneyama, M, et al. Effect of maternal stress on fetal heart rate assessed by vibroacoustic stimulation. J Int Med Res. 2009; 37, 1780–1788.Google Scholar
64. Sanders, BJ, Anticevic, A. Maternal separation enhances neuronal activation and cardiovascular responses to acute stress in borderline hypertensive rats. Behav Brain Res. 2007; 183, 25–30.Google Scholar
65. Alastalo, H, Raikkonen, K, Pesonen, AK, et al. Cardiovascular morbidity and mortality in Finnish men and women separated temporarily from their parents in childhood – a life course study. Psychosom Med. 2012; 74, 583–587.Google Scholar
66. Aragon, AC, Kopf, PG, Campen, MJ, Huwe, JK, Walker, MK. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology. Toxicol Sci. 2008; 101, 321–330.Google Scholar
67. Thackaberry, EA, Nunez, BA, Ivnitski-Steele, ID, Friggins, M, Walker, MK. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on murine heart development: alteration in fetal and postnatal cardiac growth, and postnatal cardiac chronotropy. Toxicol Sci. 2005; 88, 242–249.Google Scholar
68. Chapalamadugu, KC, Vandevoort, CA, Settles, ML, Robison, BD, Murdoch, GK. Maternal bisphenol a exposure impacts the fetal heart transcriptome. PLoS One. 2014; 9, e89096.Google Scholar
69. MohanKumar, SM, Rajendran, TD, Vyas, AK, et al. Effects of prenatal bisphenol-A exposure and postnatal overfeeding on cardiovascular function in female sheep. J Dev Orig Health Dis. 2017; 8, 65–74.Google Scholar
70. Valenzuela-Alcaraz, B, Crispi, F, Bijnens, B, et al. Assisted reproductive technologies are associated with cardiovascular remodeling in utero that persists postnatally. Circulation. 2013; 128, 1442–1450.Google Scholar
71. Scherrer, U, Rexhaj, E, Allemann, Y, Sartori, C, Rimoldi, SF. Cardiovascular dysfunction in children conceived by assisted reproductive technologies. Eur Heart J. 2015; 36, 1583–1589.Google Scholar
72. Materna-Kiryluk, A, Wisniewska, K, Badura-Stronka, M, et al. Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatr Perinat Epidemiol. 2009; 23, 29–40.Google Scholar
73. Su, XJ, Yuan, W, Huang, GY, Olsen, J, Li, J. Paternal age and offspring congenital heart defects: a national cohort study. PLoS One. 2015; 10, e0121030.Google Scholar
74. Keverne, EB. Genomic imprinting, action, and interaction of maternal and fetal genomes. Proc Natl Acad Sci U S A. 2014; 112, 6834–6840.Google Scholar
75. Hughes, V. Epigenetics: the sins of the father. Nature. 2014; 507, 22–24.Google Scholar
76. Kaati, G, Bygren, LO, Edvinsson, S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet. 2002; 10, 682–688.Google Scholar
77. Bartel, DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116, 281–297.Google Scholar
78. Martinez, SR, Gay, MS, Zhang, L. Epigenetic mechanisms in heart development and disease. Drug Discov Today. 2015; 20, 799–811.Google Scholar
79. Sandovici, I, Smith, NH, Nitert, MD, et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A. 2011; 108, 5449–5454.Google Scholar
80. Yan, S, Jiao, K. Functions of miRNAs during mammalian heart development. Int J Mol Sci. 2016; 17, 789.Google Scholar
81. Latronico, MV, Condorelli, G. MicroRNAs and cardiac pathology. Nat Rev Cardiol. 2009; 6, 419–429.Google Scholar
82. Frost, RJ, Olson, EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci U S A. 2011; 108, 21075–21080.Google Scholar
83. Trajkovski, M, Hausser, J, Soutschek, J, et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature. 2011; 474, 649–653.Google Scholar
84. Lee, CT, Risom, T, Strauss, WM. Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny. DNA Cell Biol. 2007; 26, 209–218.Google Scholar
85. Friedman, RC, Farh, KK, Burge, CB, Bartel, DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009; 19, 92–105.Google Scholar
86. Lee, Y, Kim, M, Han, J, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004; 23, 4051–4060.Google Scholar
87. Borchert, GM, Lanier, W, Davidson, BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol. 2006; 13, 1097–1101.Google Scholar
88. Han, J, Lee, Y, Yeom, KH, Kim, YK, Jin, H, Kim, VN. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004; 18, 3016–3027.Google Scholar
89. Yi, R, Qin, Y, Macara, IG, Cullen, BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003; 17, 3011–3016.Google Scholar
90. Wilson, RC, Tambe, A, Kidwell, MA, Noland, CL, Schneider, CP, Doudna, JA. Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis. Mol Cell. 2015; 57, 397–407.Google Scholar
91. Maniataki, E, Mourelatos, Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005; 19, 2979–2990.Google Scholar
92. Place, RF, Li, LC, Pookot, D, Noonan, EJ, Dahiya, R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A. 2008; 105, 1608–1613.Google Scholar
93. Bruno, IG, Karam, R, Huang, L, et al. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol Cell. 2011; 42, 500–510.Google Scholar
94. Atambayeva, S, Niyazova, R, Ivashchenko, A, et al. The binding sites of miR-619-5p in the mRNAs of human and orthologous genes. BMC Genomics. 2017; 18, 428.Google Scholar
95. Davis, CD, Ross, SA. Evidence for dietary regulation of microRNA expression in cancer cells. Nutr Rev. 2008; 66, 477–482.Google Scholar
96. Fiedler, SD, Carletti, MZ, Hong, X, Christenson, LK. Hormonal regulation of microRNA expression in periovulatory mouse mural granulosa cells. Biol Reprod. 2008; 79, 1030–1037.Google Scholar
97. Kulshreshtha, R, Ferracin, M, Negrini, M, Calin, GA, Davuluri, RV, Ivan, M. Regulation of microRNA expression: the hypoxic component. Cell Cycle. 2007; 6, 1426–1431.Google Scholar
98. Siddeek, B, Inoubli, L, Lakhdari, N, et al. MicroRNAs as potential biomarkers in diseases and toxicology. Mutat Res Genet Toxicol Environ Mutagen. 2014; 764-765, 46–57.Google Scholar
99. da Costa Martins, PA, Bourajjaj, M, Gladka, M, et al. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008; 118, 1567–1576.Google Scholar
100. Chen, JF, Murchison, EP, Tang, R, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A. 2008; 105, 2111–2116.Google Scholar
101. Saxena, A, Tabin, CJ. miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A. 2010; 107, 87–91.Google Scholar
102. Bernstein, E, Kim, SY, Carmell, MA, et al. Dicer is essential for mouse development. Nat Genet. 2003; 35, 215–217.Google Scholar
103. Wang, DZ. MicroRNAs in cardiac development and remodeling. Pediatr Cardiol. 2010; 31, 357–362.Google Scholar
104. Rottiers, V, Naar, AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol. 2012; 13, 239–250.Google Scholar
105. Yang, L, Li, Y, Wang, X, et al. Overexpression of miR-223 tips the balance of pro- and anti-hypertrophic signaling cascades toward physiologic cardiac hypertrophy. J Biol Chem. 2016; 291, 15700–15713. https://doi.org/10.1074/jbc.M116.715805.Google Scholar
106. Wang, H, Cai, J. The role of microRNAs in heart failure. Biochim Biophys Acta. 2017; 1863, 2019–2030.Google Scholar
107. Zhao, Y, Samal, E, Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005; 436, 214–220.Google Scholar
108. Qian, L, Wythe, JD, Liu, J, et al. Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. J Cell Biol. 2011; 193, 1181–1196.Google Scholar
109. Chen, J, Yin, H, Jiang, Y, et al. Induction of microRNA-1 by myocardin in smooth muscle cells inhibits cell proliferation. Arterioscler Thromb Vasc Biol. 2011; 31, 368–375.Google Scholar
110. Kwon, C, Han, Z, Olson, EN, Srivastava, D. MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci U S A. 2005; 102, 18986–18991.Google Scholar
111. Ali, R, Huang, Y, Maher, SE, et al. miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling. J Mol Cell Cardiol. 2012; 52, 1027–1037.Google Scholar
112. Zhao, Y, Ransom, JF, Li, A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129, 303–317.Google Scholar
113. Besser, J, Malan, D, Wystub, K, et al. MiRNA-1/133a clusters regulate adrenergic control of cardiac repolarization. PLoS One. 2014; 9, e113449.Google Scholar
114. Curcio, A, Torella, D, Iaconetti, C, et al. MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts. PLoS One. 2013; 8, e70158.Google Scholar
115. Rau, F, Freyermuth, F, Fugier, C, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011; 18, 840–845.Google Scholar
116. Costantino, S, Paneni, F, Luscher, TF, Cosentino, F. MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J. 2016; 37, 572–576.Google Scholar
117. De Gonzalo-Calvo, D, Van der Meer, RW, Rijzewijk, LJ, et al. Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes. Sci Rep. 2017; 7, 47.Google Scholar
118. Rawal, S, Ram, TP, Coffey, S, et al. Differential expression pattern of cardiovascular microRNAs in the human type-2 diabetic heart with normal ejection fraction. Int J Cardiol. 2016; 202, 40–43.Google Scholar
119. Zampetaki, A, Kiechl, S, Drozdov, I, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010; 107, 810–817.Google Scholar
120. Flowers, E, Aouizerat, BE, Abbasi, F, et al. Circulating microRNA-320a and microRNA-486 predict thiazolidinedione response: moving towards precision health for diabetes prevention. Metabolism. 2015; 64, 1051–1059.Google Scholar
121. Liu, X, You, L, Zhou, R, Zhang, J. Significant association between functional microRNA polymorphisms and coronary heart disease susceptibility: a comprehensive meta-analysis involving 16484 subjects. Oncotarget. 2017; 8, 5692–5702.Google Scholar
122. Lock, MC, Botting, KJ, Tellam, RL, Brooks, D, Morrison, JL. Adverse intrauterine environment and cardiac miRNA expression. Int J Mol Sci. 2017; 18, 2628.Google Scholar
123. Martinez, SR, Ma, Q, Dasgupta, C, Meng, X, Zhang, L. MicroRNA-210 suppresses glucocorticoid receptor expression in response to hypoxia in fetal rat cardiomyocytes. Oncotarget. 2017; 8, 80249–80264.Google Scholar
124. Chan, YC, Banerjee, J, Choi, SY, Sen, CK. miR-210: the master hypoxamir. Microcirculation. 2012; 19, 215–223.Google Scholar
125. Huang, X, Zuo, J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim Biophys Sin (Shanghai). 2014; 46, 220–232.Google Scholar
126. Guan, J, Long, K, Ma, J, et al. Comparative analysis of the microRNA transcriptome between yak and cattle provides insight into high-altitude adaptation. PeerJ. 2017; 5, e3959.Google Scholar
127. El Azzouzi, H, Leptidis, S, Dirkx, E, et al. The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARdelta and impairs mitochondrial fatty acid oxidation. Cell Metab. 2013; 18, 341–354.Google Scholar
128. Maloyan, A, Muralimanoharan, S, Huffman, S, et al. Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity. Physiol Genomics. 2013; 45, 889–900.Google Scholar
129. Kuwabara, Y, Horie, T, Baba, O, et al. MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ Res. 2015; 116, 279–288.Google Scholar
130. Guedes, EC, Franca, GS, Lino, CA, et al. MicroRNA expression signature is altered in the cardiac remodeling induced by high fat diets. J Cell Physiol. 2016; 231, 1771–1783.Google Scholar
131. Floris, I, Descamps, B, Vardeu, A, et al. Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2. Arterioscler Thromb Vasc Biol. 2015; 35, 664–674.Google Scholar
132. Siddeek, B, Lakhdari, N, Inoubli, L, et al. Developmental epigenetic programming of adult germ cell death disease: polycomb protein EZH2-miR-101 pathway. Epigenomics. 2016; 8, 1459–1479.Google Scholar
133. Fernandez-Twinn, DS, Blackmore, HL, Siggens, L, et al. The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation. Endocrinology. 2012; 153, 5961–5971.Google Scholar
134. Wing-Lun, E, Eaton, SA, Hur, SS, et al. Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice. Epigenetics. 2016; 11, 475–481.Google Scholar
135. Grueter, CE, Van Rooij, E, Johnson, BA, et al. A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell. 2012; 149, 671–683.Google Scholar
136. Zhu, C, Yu, ZB, Zhu, JG, et al. Differential expression profile of MicroRNAs during differentiation of cardiomyocytes exposed to polychlorinated biphenyls. Int J Mol Sci. 2012; 13, 15955–15966.Google Scholar
137. Christopher, AF, Kaur, RP, Kaur, G, Kaur, A, Gupta, V, Bansal, P. MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res. 2016; 7, 68–74.Google Scholar
138. Rupaimoole, R, Slack, FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017; 16, 203–222.Google Scholar
139. Montgomery, RL, Hullinger, TG, Semus, HM, et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation. 2011; 124, 1537–1547.Google Scholar
140. Rayner, KJ, Sheedy, FJ, Esau, CC, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011; 121, 2921–2931.Google Scholar
141. Zeng, XC, Li, L, Wen, H, Bi, Q. MicroRNA-128 inhibition attenuates myocardial ischemia/reperfusion injury-induced cardiomyocyte apoptosis by the targeted activation of peroxisome proliferator-activated receptor gamma. Mol Med Rep. 2016; 14, 129–136.Google Scholar
142. Jiang, C, Ji, N, Luo, G, et al. The effects and mechanism of miR-92a and miR-126 on myocardial apoptosis in mouse ischemia-reperfusion model. Cell Biochem Biophys. 2014; 70, 1901–1906.Google Scholar
143. Zhang, Y, Qin, W, Zhang, L, et al. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis. Sci Rep. 2015; 5, 9401.Google Scholar
144. Hullinger, TG, Montgomery, RL, Seto, AG, et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012; 110, 71–81.Google Scholar
145. Bernardo, BC, Gao, XM, Winbanks, CE, et al. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A. 2012; 109, 17615–17620.Google Scholar
146. Li, J, Li, Y, Jiao, J, et al. Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis. Mol Cell Biol. 2014; 34, 1788–1799.Google Scholar
147. Bonci, D. MicroRNA-21 as therapeutic target in cancer and cardiovascular disease. Recent Pat Cardiovasc Drug Discov. 2010; 5, 156–161.Google Scholar
148. Wahlquist, C, Jeong, D, Rojas-Munoz, A, et al. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature. 2014; 508, 531–535.Google Scholar
149. Hu, S, Huang, M, Li, Z, et al. MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation. 2010; 122(Suppl.), S124–S131.Google Scholar
150. Wang, Y, Zhang, L, Li, Y, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol. 2015; 192, 61–69.Google Scholar
151. Andrade, DC, Arce-Alvarez, A, Toledo, C, et al. Exercise training improve cardiac autonomic control, cardiac function and arrhythmogenesis in rats with preserved ejection fraction heart failure. J Appl Physiol (1985). 2017; 123, 567–577.Google Scholar
152. Denham, J, Prestes, PR. Muscle-enriched microRNAs isolated from whole blood are regulated by exercise and are potential biomarkers of cardiorespiratory fitness. Front Genet. 2016; 7, 196.Google Scholar
153. Zhao, Y, Ma, Z. Swimming training affects apoptosis-related microRNAs and reduces cardiac apoptosis in mice. Gen Physiol Biophys. 2016; 35, 443–450.Google Scholar
154. Lew, JK, Pearson, JT, Schwenke, DO, Katare, R. Exercise mediated protection of diabetic heart through modulation of microRNA mediated molecular pathways. Cardiovasc Diabetol. 2017; 16, 10.Google Scholar
155. Melo, SF, Barauna, VG, Neves, VJ, et al. Exercise training restores the cardiac microRNA-1 and -214 levels regulating Ca2+ handling after myocardial infarction. BMC Cardiovasc Disord. 2015; 15, 166.Google Scholar
156. Barr, LA, Shimizu, Y, Lambert, JP, Nicholson, CK, Calvert, JW. Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress. Nitric Oxide. 2015; 46, 145–156.Google Scholar
157. Khatua, TN, Adela, R, Banerjee, SK. Garlic and cardioprotection: insights into the molecular mechanisms. Can J Physiol Pharmacol. 2013; 91, 448–458.Google Scholar
158. Jain, SK, Bull, R, Rains, JL, et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal. 2010; 12, 1333–1337.Google Scholar
159. Peh, MT, Anwar, AB, Ng, DS, Atan, MS, Kumar, SD, Moore, PK. Effect of feeding a high fat diet on hydrogen sulfide (H2S) metabolism in the mouse. Nitric Oxide. 2014; 41, 138–145.Google Scholar
160. Kesherwani, V, Nandi, SS, Sharawat, SK, Shahshahan, HR, Mishra, PK. Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes. Mol Cell Biochem. 2015; 404, 241–250.Google Scholar
161. Kang, B, Hong, J, Xiao, J, et al. Involvement of miR-1 in the protective effect of hydrogen sulfide against cardiomyocyte apoptosis induced by ischemia/reperfusion. Mol Biol Rep. 2014; 41, 6845–6853.Google Scholar
162. Gray, C, Li, M, Patel, R, Reynolds, CM, Vickers, MH. Let-7 miRNA profiles are associated with the reversal of left ventricular hypertrophy and hypertension in adult male offspring from mothers undernourished during pregnancy after preweaning growth hormone treatment. Endocrinology. 2014; 155, 4808–4817.Google Scholar
163. Li, N, Guenancia, C, Rigal, E, et al. Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice. Sci Rep. 2016; 6, 30817.Google Scholar
164. Sygitowicz, G, Tomaniak, M, Blaszczyk, O, Koltowski, L, Filipiak, KJ, Sitkiewicz, D. Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: preliminary results. Arch Cardiovasc Dis. 2015; 108, 634–642.Google Scholar
165. Naga Prasad, SV, Gupta, MK, Duan, ZH, et al. A unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. PloS One. 2017; 12, e0170456.Google Scholar
166. Su, X, Liang, H, Wang, H, et al. Over-expression of microRNA-1 causes arrhythmia by disturbing intracellular trafficking system. Sci Rep. 2017; 7, 46259.Google Scholar
167. Yang, B, Lin, H, Xiao, J, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007; 13, 486–491.Google Scholar
168. Navickas, R, Gal, D, Laucevicius, A, Taparauskaite, A, Zdanyte, M, Holvoet, P. Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review. Cardiovasc Res. 2016; 111, 322–337.Google Scholar
169. Liu, L, Yuan, Y, He, X, Xia, X, Mo, X. MicroRNA-1 upregulation promotes myocardiocyte proliferation and suppresses apoptosis during heart development. Mol Med Rep. 2017; 15, 2837–2842.Google Scholar
170. Jung, S, Bohan, A. Genome-wide sequencing and quantification of circulating microRNAs for dogs with congestive heart failure secondary to myxomatous mitral valve degeneration. Am J Vet Res. 2018; 79, 163–169.Google Scholar
171. Luo, S, Chen, Y, He, R, Shi, Y, Su, L. Rescuing infusion of miRNA-1 prevents cardiac remodeling in a heart-selective miRNA deficient mouse. Biochem Biophys Res Commun. 2018; 495, 607–613.Google Scholar
172. Tatsuguchi, M, Seok, HY, Callis, TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2007; 42, 1137–1141.Google Scholar
173. Long, G, Wang, F, Duan, Q, et al. Human circulating microRNA-1 and microRNA-126 as potential novel indicators for acute myocardial infarction. Int J Biol Sci. 2012; 8, 811–818.Google Scholar
174. Cheng, Y, Tan, N, Yang, J, et al. A translational study of circulating cell-free microRNA-1 in acute myocardial infarction. Clin Sci. 2010; 119, 87–95.Google Scholar
175. Yang, VK, Tai, AK, Huh, TP, et al. Dysregulation of valvular interstitial cell let-7c, miR-17, miR-20a, and miR-30d in naturally occurring canine myxomatous mitral valve disease. PLoS One. 2018; 13, e0188617.Google Scholar
176. Marques, FZ, Vizi, D, Khammy, O, Mariani, JA, Kaye, DM. The transcardiac gradient of cardio-microRNAs in the failing heart. Eur J Heart Fail. 2016; 18, 1000–1008.Google Scholar
177. Faccini, J, Ruidavets, JB, Cordelier, P, et al. Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease. Sci Rep. 2017; 7, 42916.Google Scholar
178. Cao, L, Kong, LP, Yu, ZB, et al. microRNA expression profiling of the developing mouse heart. Int J Mol Med. 2012; 30, 1095–1104.Google Scholar
179. Wang, H, Shi, J, Li, B, Zhou, Q, Kong, X, Bei, Y. MicroRNA expression signature in human calcific aortic valve disease. Biomed Res Int. 2017; 2017, 4820275.Google Scholar
180. Wang, X, Wang, HX, Li, YL, et al. MicroRNA Let-7i negatively regulates cardiac inflammation and fibrosis. Hypertension. 2015; 66, 776–785.Google Scholar
181. Lu, Y, Hou, S, Huang, D, et al. Expression profile analysis of circulating microRNAs and their effects on ion channels in Chinese atrial fibrillation patients. Int J Clin Exp Med. 2015; 8, 845–853.Google Scholar
182. Wang, L, Ma, L, Fan, H, Yang, Z, Li, L, Wang, H. MicroRNA-9 regulates cardiac fibrosis by targeting PDGFR-beta in rats. J Physiol Biochem. 2016; 72, 213–223.Google Scholar
183. Wang, K, Long, B, Zhou, J, Li, PF. miR-9 and NFATc3 regulate myocardin in cardiac hypertrophy. J Biol Chem. 2010; 285, 11903–11912.Google Scholar
184. Jeyabal, P, Thandavarayan, RA, Joladarashi, D, et al. MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem Biophys Res Commun. 2016; 471, 423–429.Google Scholar
185. Luo, L, Chen, B, Li, S, et al. Plasma miR-10a: a potential biomarker for coronary artery disease. Dis Markers. 2016; 2016, 3841927.Google Scholar
186. Chen, F, Zhao, X, Peng, J, Bo, L, Fan, B, Ma, D. Integrated microRNA-mRNA analysis of coronary artery disease. Mol Biol Rep. 2014; 41, 5505–5511.Google Scholar
187. Danielson, LS, Park, DS, Rotllan, N, et al. Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis. FASEB J. 2013; 27, 1460–1467.Google Scholar
188. Liu, F, Li, R, Zhang, Y, Qiu, J, Ling, W. Association of plasma MiR-17-92 with dyslipidemia in patients with coronary artery disease. Medicine (Baltimore). 2014; 93, e98.Google Scholar
189. Bai, Y, Wang, J, Morikawa, Y, Bonilla-Claudio, M, Klysik, E, Martin, JF. Bmp signaling represses Vegfa to promote outflow tract cushion development. Development. 2013; 140, 3395–3402.Google Scholar
190. Ventura, A, Young, AG, Winslow, MM, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008; 132, 875–886.Google Scholar
191. Van Almen, GC, Verhesen, W, Van Leeuwen, RE, et al. MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging Cell. 2011; 10, 769–779.Google Scholar
192. Benz, A, Kossack, M, Auth, D, et al. miR-19b regulates ventricular action potential duration in zebrafish. Sci Rep. 2016; 6, 36033.Google Scholar
193. Zeller, T, Keller, T, Ojeda, F, et al. Assessment of microRNAs in patients with unstable angina pectoris. Eur Heart J. 2014; 35, 2106–2114.Google Scholar
194. Song, DW, Ryu, JY, Kim, JO, Kwon, EJ, Kim, DH. The miR-19a/b family positively regulates cardiomyocyte hypertrophy by targeting atrogin-1 and MuRF-1. Biochem J. 2014; 457, 151–162.Google Scholar
195. Zhong, J, He, Y, Chen, W, Shui, X, Chen, C, Lei, W. Circulating microRNA-19a as a potential novel biomarker for diagnosis of acute myocardial infarction. Int J Mol Sci. 2014; 15, 20355–20364.Google Scholar
196. Copier, CU, Leon, L, Fernandez, M, Contador, D, Calligaris, SD. Circulating miR-19b and miR-181b are potential biomarkers for diabetic cardiomyopathy. Sci Rep. 2017; 7, 13514.Google Scholar
197. Lin, J, Xue, A, Li, L, et al. MicroRNA-19b downregulates gap junction protein alpha1 and synergizes with microRNA-1 in viral myocarditis. Int J Mol Sci. 2016; 17, 741.Google Scholar
198. Xu, HF, Gao, XT, Lin, JY, et al. MicroRNA-20b suppresses the expression of ZFP-148 in viral myocarditis. Mol Cell Biochem. 2017; 429, 199–210.Google Scholar
199. Barana, A, Matamoros, M, Dolz-Gaiton, P, et al. Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ Arrhythm Electrophysiol. 2014; 7, 861–868.Google Scholar
200. Wang, F, Long, G, Zhao, C, et al. Atherosclerosis-related circulating miRNAs as novel and sensitive predictors for acute myocardial infarction. PLoS One. 2014; 9, e105734.Google Scholar
201. Kolpa, HJ, Peal, DS, Lynch, SN, et al. miR-21 represses Pdcd4 during cardiac valvulogenesis. Development. 2013; 140, 2172–2180.Google Scholar
202. Thum, T, Gross, C, Fiedler, J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008; 456, 980–984.Google Scholar
203. Shen, E, Diao, X, Wang, X, Chen, R, Hu, B. MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy. Am J Pathol. 2011; 179, 639–650.Google Scholar
204. Xu, HF, Ding, YJ, Zhang, ZX, et al. MicroRNA21 regulation of the progression of viral myocarditis to dilated cardiomyopathy. Mol Med Rep. 2014; 10, 161–168.Google Scholar
205. Corsten, MF, Papageorgiou, A, Verhesen, W, et al. MicroRNA profiling identifies microRNA-155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis. Circ Res. 2012; 111, 415–425.Google Scholar
206. Van Boven, N, Akkerhuis, KM, Anroedh, SS, et al. Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients with chronic heart failure: the Bio-SHiFT study. Int J Cardiol. 2017; 235, 124–132.Google Scholar
207. Hong, Y, Cao, H, Wang, Q, et al. MiR-22 may suppress fibrogenesis by targeting TGFbetaR I in cardiac fibroblasts. Cell Physiol Biochem. 2016; 40, 1345–1353.Google Scholar
208. Maciejak, A, Kiliszek, M, Opolski, G, et al. miR-22-5p revealed as a potential biomarker involved in the acute phase of myocardial infarction via profiling of circulating microRNAs. Mol Med Rep. 2016; 14, 2867–2875.Google Scholar
209. Lagendijk, AK, Goumans, MJ, Burkhard, SB, Bakkers, J. MicroRNA-23 restricts cardiac valve formation by inhibiting Has2 and extracellular hyaluronic acid production. Circ Res. 2011; 109, 649–657.Google Scholar
210. Van Rooij, E, Sutherland, LB, Liu, N, et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006; 103, 18255–18260.Google Scholar
211. Chen, Z, Lu, S, Xu, M, Liu, P, Ren, R, Ma, W. Role of miR-24, furin, and transforming growth factor-beta1 signal pathway in fibrosis after cardiac infarction. Med Sci Monit. 2017; 23, 65–70.Google Scholar
212. Dirkx, E, Gladka, MM, Philippen, LE, et al. Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. Nat Cell Biol. 2013; 15, 1282–1293.Google Scholar
213. Luo, X, Pan, Z, Shan, H, et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest. 2013; 123, 1939–1951.Google Scholar
214. Nigam, V, Sievers, HH, Jensen, BC, et al. Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. J Heart Valve Dis. 2010; 19, 459–465.Google Scholar
215. Xu, HX, Wang, Y, Zheng, DD, et al. Differential expression of microRNAs in calcific aortic stenosis. Clin Lab. 2017; 63, 1163–1170.Google Scholar
216. Wei, C, Kim, IK, Kumar, S, et al. NF-kappaB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol. 2013; 228, 1433–1442.Google Scholar
217. Han, M, Yang, Z, Sayed, D, et al. GATA4 expression is primarily regulated via a miR-26b-dependent post-transcriptional mechanism during cardiac hypertrophy. Cardiovasc Res. 2012; 93, 645–654.Google Scholar
218. Li, C, Chen, X, Huang, J, Sun, Q, Wang, L. Clinical impact of circulating miR-26a, miR-191, and miR-208b in plasma of patients with acute myocardial infarction. Eur J Med Res. 2015; 20, 58.Google Scholar
219. Takahashi, K, Sasano, T, Sugiyama, K, et al. High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b. J Mol Cell Cardiol. 2016; 90, 38–46.Google Scholar
220. Yu, K, Ji, Y, Wang, H, et al. Association of miR-196a2, miR-27a, and miR-499 polymorphisms with isolated congenital heart disease in a Chinese population. Genet Mol Res. 2016; 15, gmr15048929.Google Scholar
221. O’Brien, JE Jr., Kibiryeva, N, Zhou, XG, et al. Noncoding RNA expression in myocardium from infants with tetralogy of Fallot. Circ Cardiovasc Genet. 2012; 5, 279–286.Google Scholar
222. Wang, J, Song, Y, Zhang, Y, et al. Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice. Cell Res. 2012; 22, 516–527.Google Scholar
223. Wang, Y, Chen, S, Gao, Y, Zhang, S. Serum MicroRNA-27b as a screening biomarker for left ventricular hypertrophy. Tex Heart Inst J. 2017; 44, 385–389.Google Scholar
224. Zhu, S, Cao, L, Zhu, J, et al. Identification of maternal serum microRNAs as novel non-invasive biomarkers for prenatal detection of fetal congenital heart defects. Clin Chim Acta. 2013; 424, 66–72.Google Scholar
225. Shi, J, Liu, H, Wang, H, Kong, X. MicroRNA expression signature in degenerative aortic stenosis. Biomed Res Int. 2016; 2016, 4682172.Google Scholar
226. Van Rooij, E, Sutherland, LB, Thatcher, JE, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008; 105, 13027–13032.Google Scholar
227. Sassi, Y, Avramopoulos, P, Ramanujam, D, et al. Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling. Nat Commun. 2017; 8, 1614.Google Scholar
228. Li, H, Li, S, Yu, B, Liu, S. Expression of miR-133 and miR-30 in chronic atrial fibrillation in canines. Mol Med Rep. 2012; 5, 1457–1460.Google Scholar
229. Liu, X, Li, M, Peng, Y, et al. miR-30c regulates proliferation, apoptosis and differentiation via the Shh signaling pathway in P19 cells. Exp Mol Med. 2016; 48, e248.Google Scholar
230. Duisters, RF, Tijsen, AJ, Schroen, B, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res. 2009; 104, 170–178, 176p following 178.Google Scholar
231. Pan, W, Zhong, Y, Cheng, C, et al. MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy. PLoS One. 2013; 8, e53950.Google Scholar
232. Meder, B, Keller, A, Vogel, B, et al. MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction. Basic Res Cardiol. 2011; 106, 13–23.Google Scholar
233. Zhang, X, Fernandez-Hernando, C. miR-33 regulation of adaptive fibrotic response in cardiac remodeling. Circ Res. 2017; 120, 753–755.Google Scholar
234. Gacon, J, Kablak-Ziembicka, A, Stepien, E, et al. Decision-making microRNAs (miR-124, -133a/b, -34a and -134) in patients with occluded target vessel in acute coronary syndrome. Kardiol Pol. 2016; 74, 280–288.Google Scholar
235. Boon, RA, Iekushi, K, Lechner, S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013; 495, 107–110.Google Scholar
236. Huang, J, Sun, W, Huang, H, et al. miR-34a modulates angiotensin II-induced myocardial hypertrophy by direct inhibition of ATG9A expression and autophagic activity. PLoS One. 2014; 9, e94382.Google Scholar
237. Greco, S, Fasanaro, P, Castelvecchio, S, et al. MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes. 2012; 61, 1633–1641.Google Scholar
238. Niculescu, LS, Simionescu, N, Sanda, GM, et al. MiR-486 and miR-92a identified in circulating HDL discriminate between stable and vulnerable coronary artery disease patients. PLoS One. 2015; 10, e0140958.Google Scholar
239. Taurino, C, Miller, WH, McBride, MW, et al. Gene expression profiling in whole blood of patients with coronary artery disease. Clin Sci (Lond). 2010; 119, 335–343.Google Scholar
240. Catalucci, D, Latronico, MV, Condorelli, G. MicroRNAs control gene expression: importance for cardiac development and pathophysiology. Ann N Y Acad Sci. 2008; 1123, 20–29.Google Scholar
241. JF, OS, Neylon, A, McGorrian, C, Blake, GJ. miRNA-93-5p and other miRNAs as predictors of coronary artery disease and STEMI. Int J Cardiol. 2016; 224, 310–316.Google Scholar
242. Li, Q, Freeman, LM, Rush, JE, Laflamme, DP. Expression profiling of circulating microRNAs in canine myxomatous mitral valve disease. Int J Mol Sci. 2015; 16, 14098–14108.Google Scholar
243. Yang, Y, Ago, T, Zhai, P, Abdellatif, M, Sadoshima, J. Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7. Circ Res. 2011; 108, 305–313.Google Scholar
244. Natsume, Y, Oaku, K, Takahashi, K, et al. Combined analysis of human and experimental murine samples identified novel circulating microRNAs as biomarkers for atrial fibrillation. Circ J. 2018; 82, 965–973.Google Scholar
245. Kehler, L, Biro, O, Lazar, L, Rigo, J Jr., Nagy, B. Elevated hsa-miR-99a levels in maternal plasma may indicate congenital heart defects. Biomed Rep. 2015; 3, 869–873.Google Scholar
246. Sucharov, C, Bristow, MR, Port, JD. miRNA expression in the failing human heart: functional correlates. J Mol Cell Cardiol. 2008; 45, 185–192.Google Scholar
247. Pan, Z, Sun, X, Shan, H, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-beta1 pathway. Circulation. 2012; 126, 840–850.Google Scholar
248. Wei, L, Yuan, M, Zhou, R, et al. MicroRNA-101 inhibits rat cardiac hypertrophy by targeting Rab1a. J Cardiovasc Pharmacol. 2015; 65, 357–363.Google Scholar
249. Chiang, DY, Kongchan, N, Beavers, DL, et al. Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol. 2014; 7, 1214–1222.Google Scholar
250. Gao, W, He, HW, Wang, ZM, et al. Plasma levels of lipometabolism-related miR-122 and miR-370 are increased in patients with hyperlipidemia and associated with coronary artery disease. Lipids Health Dis. 2012; 11, 55.Google Scholar
251. Martinez-Micaelo, N, Beltran-Debon, R, Baiges, I, Faiges, M, Alegret, JM. Specific circulating microRNA signature of bicuspid aortic valve disease. J Transl Med. 2017; 15, 76.Google Scholar
252. Beaumont, J, Lopez, B, Hermida, N, et al. microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-beta1 up-regulation. Clin Sci (Lond). 2014; 126, 497–506.Google Scholar
253. D’Alessandra, Y, Devanna, P, Limana, F, et al. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J. 2010; 31, 2765–2773.Google Scholar
254. Kuhn, DE, Nuovo, GJ, Martin, MM, et al. Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts. Biochem Biophys Res Commun. 2008; 370, 473–477.Google Scholar
255. Liu, H, Qin, H, Chen, GX, et al. Comparative expression profiles of microRNA in left and right atrial appendages from patients with rheumatic mitral valve disease exhibiting sinus rhythm or atrial fibrillation. J Transl Med. 2014; 12, 90.Google Scholar
256. Nagpal, V, Rai, R, Place, AT, et al. MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis. Circulation. 2016; 133, 291–301.Google Scholar
257. Fukushima, Y, Nakanishi, M, Nonogi, H, Goto, Y, Iwai, N. Assessment of plasma miRNAs in congestive heart failure. Circ J. 2011; 75, 336–340.Google Scholar
258. Wang, X, Lian, Y, Wen, X, et al. Expression of miR-126 and its potential function in coronary artery disease. Afr Health Sci. 2017; 17, 474–480.Google Scholar
259. Zampetaki, A, Willeit, P, Tilling, L, et al. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol. 2012; 60, 290–299.Google Scholar
260. Li, L, Bounds, KR, Chatterjee, P, Gupta, S. MicroRNA-130a, a potential antifibrotic target in cardiac fibrosis. J Am Heart Assoc. 2017; 6, e006763.Google Scholar
261. Qiao, G, Xia, D, Cheng, Z, Zhang, G. miR132 in atrial fibrillation directly targets connective tissue growth factor. Mol Med Rep. 2017; 16, 4143–4150.Google Scholar
262. Ucar, A, Gupta, SK, Fiedler, J, et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun. 2012; 3, 1078.Google Scholar
263. Wen, P, Song, D, Ye, H, et al. Circulating MiR-133a as a biomarker predicts cardiac hypertrophy in chronic hemodialysis patients. PLoS One. 2014; 9, e103079.Google Scholar
264. Belevych, AE, Sansom, SE, Terentyeva, R, et al. MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLoS One. 2011; 6, e28324.Google Scholar
265. Liu, N, Bezprozvannaya, S, Williams, AH, et al. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008; 22, 3242–3254.Google Scholar
266. Care, A, Catalucci, D, Felicetti, F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007; 13, 613–618.Google Scholar
267. He, F, Lv, P, Zhao, X, et al. Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction. Mol Cell Biochem. 2014; 394, 137–144.Google Scholar
268. Yanagawa, B, Lovren, F, Pan, Y, et al. miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. J Thorac Cardiovasc Surg. 2012; 144, 256–262.Google Scholar
269. Baseler, WA, Thapa, D, Jagannathan, R, Dabkowski, ER, Croston, TL, Hollander, JM. miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart. Am J Physiol Cell Physiol. 2012; 303, C1244–C1251.Google Scholar
270. Fichtlscherer, S, De Rosa, S, Fox, H, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010; 107, 677–684.Google Scholar
271. Fernandes, T, Hashimoto, NY, Magalhaes, FC, et al. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension. 2011; 58, 182–189.Google Scholar
272. Yu, M, Liu, Y, Zhang, B, Shi, Y, Cui, L, Zhao, X. Inhibiting microRNA-144 abates oxidative stress and reduces apoptosis in hearts of streptozotocin-induced diabetic mice. Cardiovasc Pathol. 2015; 24, 375–381.Google Scholar
273. Cha, MJ, Jang, JK, Ham, O, et al. MicroRNA-145 suppresses ROS-induced Ca2+ overload of cardiomyocytes by targeting CaMKIIdelta. Biochem Biophys Res Commun. 2013; 435, 720–726.Google Scholar
274. Li, R, Yan, G, Zhang, Q, et al. miR-145 inhibits isoproterenol-induced cardiomyocyte hypertrophy by targeting the expression and localization of GATA6. FEBS Lett. 2013; 587, 1754–1761.Google Scholar
275. Van de Vrie, M, Heymans, S, Schroen, B. MicroRNA involvement in immune activation during heart failure. Cardiovasc Drugs Ther. 2011; 25, 161–170.Google Scholar
276. Liu, Z, Zhou, C, Liu, Y, et al. The expression levels of plasma micoRNAs in atrial fibrillation patients. PLoS One. 2012; 7, e44906.Google Scholar
277. Oerlemans, MI, Mosterd, A, Dekker, MS, et al. Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs. EMBO Mol Med. 2012; 4, 1176–1185.Google Scholar
278. Huang, W, Tian, SS, Hang, PZ, Sun, C, Guo, J, Du, ZM. Combination of microRNA-21 and microRNA-146a attenuates cardiac dysfunction and apoptosis during acute myocardial infarction in mice. Mol Ther Nucleic Acids. 2016; 5, e296.Google Scholar
279. Patel, V, Carrion, K, Hollands, A, et al. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF-kappaB signaling, and inflammatory gene expression in human aortic valve cells. FASEB J. 2015; 29, 1859–1868.Google Scholar
280. Bao, JL, Lin, L. MiR-155 and miR-148a reduce cardiac injury by inhibiting NF-kappaB pathway during acute viral myocarditis. Eur Rev Med Pharmacol Sci. 2014; 18, 2349–2356.Google Scholar
281. Ali Sheikh, MS, Xia, K, Li, F, et al. Circulating miR-765 and miR-149: potential noninvasive diagnostic biomarkers for geriatric coronary artery disease patients. Biomed Res Int. 2015; 2015, 740301.Google Scholar
282. Sayed, AS, Xia, K, Li, F, et al. The diagnostic value of circulating microRNAs for middle-aged (40-60-year-old) coronary artery disease patients. Clinics (Sao Paulo). 2015; 70, 257–263.Google Scholar
283. Liu, W, Liu, Y, Zhang, Y, et al. MicroRNA-150 protects against pressure overload-induced cardiac hypertrophy. J Cell Biochem. 2015; 116, 2166–2176.Google Scholar
284. Zhang, R, Lan, C, Pei, H, Duan, G, Huang, L, Li, L. Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction. BMC Cardiovasc Disord. 2015; 15, 51.Google Scholar
285. Zhang, D, Cui, Y, Li, B, Luo, X, Li, B, Tang, Y. miR-155 regulates high glucose-induced cardiac fibrosis via the TGF-beta signaling pathway. Mol Biosyst. 2016; 13, 215–224.Google Scholar
286. Seok, HY, Chen, J, Kataoka, M, et al. Loss of microRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res. 2014; 114, 1585–1595.Google Scholar
287. Li, J, Cao, Y, Ma, XJ, et al. Roles of miR-1-1 and miR-181c in ventricular septal defects. Int J Cardiol. 2013; 168, 1441–1446.Google Scholar
288. Zhu, J, Yao, K, Wang, Q, et al. Circulating miR-181a as a potential novel biomarker for diagnosis of acute myocardial infarction. Cell Physiol Biochem. 2016; 40, 1591–1602.Google Scholar
289. Kim, JO, Song, DW, Kwon, EJ, et al. miR-185 plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways. PLoS One. 2015; 10, e0122509.Google Scholar
290. Wang, K, Liu, CY, Zhou, LY, et al. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun. 2015; 6, 6779.Google Scholar
291. Wong, LL, Armugam, A, Sepramaniam, S, et al. Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 2015; 17, 393–404.Google Scholar
292. Hang, P, Sun, C, Guo, J, Zhao, J, Du, Z. BDNF-mediates down-regulation of microRNA-195 inhibits ischemic cardiac apoptosis in rats. Int J Biol Sci. 2016; 12, 979–989.Google Scholar
293. Zheng, D, Ma, J, Yu, Y, et al. Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia. 2015; 58, 1949–1958.Google Scholar
294. Schulte, C, Molz, S, Appelbaum, S, et al. miRNA-197 and miRNA-223 predict cardiovascular death in a cohort of patients with symptomatic coronary artery disease. PLoS One. 2015; 10, e0145930.Google Scholar
295. Li, Z, Song, Y, Liu, L, et al. miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation. Cell Death Differ. 2017; 24, 1205–1213.Google Scholar
296. Lesizza, P, Prosdocimo, G, Martinelli, V, Sinagra, G, Zacchigna, S, Giacca, M. Single-dose intracardiac injection of pro-regenerative microRNAs improves cardiac function after myocardial infarction. Circ Res. 2017; 120, 1298–1304.Google Scholar
297. Vogel, B, Keller, A, Frese, KS, et al. Multivariate miRNA signatures as biomarkers for non-ischaemic systolic heart failure. Eur Heart J. 2013; 34, 2812–2822.Google Scholar
298. Feng, B, Cao, Y, Chen, S, Chu, X, Chu, Y, Chakrabarti, S. miR-200b mediates endothelial-to-mesenchymal transition in diabetic cardiomyopathy. Diabetes. 2016; 65, 768–779.Google Scholar
299. Chen, YT, Wang, J, Wee, AS, et al. Differential microRNA expression profile in myxomatous mitral valve prolapse and fibroelastic deficiency valves. Int J Mol Sci. 2016; 17, 753.Google Scholar
300. Song, R, Fullerton, DA, Ao, L, et al. Altered microRNA expression is responsible for the pro-osteogenic phenotype of interstitial cells in calcified human aortic valves. J Am Heart Assoc. 2017; 6, e005364.Google Scholar
301. Zhang, Y, Zheng, S, Geng, Y, et al. MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. PLoS One. 2015; 10, e0122674.Google Scholar
302. Wang, M, Ji, Y, Cai, S, Ding, W. MiR-206 suppresses the progression of coronary artery disease by modulating vascular endothelial growth factor (VEGF) expression. Med Sci Monit. 2016; 22, 5011–5020.Google Scholar
303. Limana, F, Esposito, G, D’Arcangelo, D, et al. HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3. PLoS One. 2011; 6, e19845.Google Scholar
304. Yang, Y, Del, Re DP, Nakano, N, et al. miR-206 mediates YAP-induced cardiac hypertrophy and survival. Circ Res. 2015; 117, 891–904.Google Scholar
305. Shan, ZX, Lin, QX, Deng, CY, et al. miR-1/miR-206 regulate Hsp60 expression contributing to glucose-mediated apoptosis in cardiomyocytes. FEBS Lett. 2010; 584, 3592–3600.Google Scholar
306. Callis, TE, Pandya, K, Seok, HY, et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009; 119, 2772–2786.Google Scholar
307. Liu, H, Yang, N, Fei, Z, et al. Analysis of plasma miR-208a and miR-370 expression levels for early diagnosis of coronary artery disease. Biomed Rep. 2016; 5, 332–336.Google Scholar
308. Wang, BW, Wu, GJ, Cheng, WP, Shyu, KG. MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart. PLoS One. 2014; 9, e84188.Google Scholar
309. Ji, X, Takahashi, R, Hiura, Y, Hirokawa, G, Fukushima, Y, Iwai, N. Plasma miR-208 as a biomarker of myocardial injury. Clin Chem. 2009; 55, 1944–1949.Google Scholar
310. Corsten, MF, Dennert, R, Jochems, S, et al. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 2010; 3, 499–506.Google Scholar
311. Arif, M, Pandey, R, Alam, P, et al. MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents. J Mol Med (Berl). 2017; 95, 1369–1385.Google Scholar
312. Xiao, J, Liang, D, Zhang, Y, et al. MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics. 2011; 43, 655–664.Google Scholar
313. Dong, H, Dong, S, Zhang, L, et al. MicroRNA-214 exerts a Cardio-protective effect by inhibition of fibrosis. Anat Rec (Hoboken). 2016; 299, 1348–1357.Google Scholar
314. Yang, X, Qin, Y, Shao, S, et al. MicroRNA-214 inhibits left ventricular remodeling in an acute myocardial infarction rat model by suppressing cellular apoptosis via the phosphatase and tensin homolog (PTEN). Int Heart J. 2016; 57, 247–250.Google Scholar
315. Minami, Y, Satoh, M, Maesawa, C, et al. Effect of atorvastatin on microRNA 221/222 expression in endothelial progenitor cells obtained from patients with coronary artery disease. Eur J Clin Invest. 2009; 39, 359–367.Google Scholar
316. Verjans, R, Peters, T, Beaumont, FJ, et al. MicroRNA-221/222 family counteracts myocardial fibrosis in pressure overload-induced heart failure. Hypertension. 2018; 71, 280–288.Google Scholar
317. Coskunpinar, E, Cakmak, HA, Kalkan, AK, Tiryakioglu, NO, Erturk, M, Ongen, Z. Circulating miR-221-3p as a novel marker for early prediction of acute myocardial infarction. Gene. 2016; 591, 90–96.Google Scholar
318. Corsten, M, Heggermont, W, Papageorgiou, AP, et al. The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis. Eur Heart J. 2015; 36, 2909–2919.Google Scholar
319. Li, D, Ji, L, Liu, L, et al. Characterization of circulating microRNA expression in patients with a ventricular septal defect. PLoS One. 2014; 9, e106318.Google Scholar
320. Song, CL, Liu, B, Diao, HY, et al. Down-regulation of microRNA-320 suppresses cardiomyocyte apoptosis and protects against myocardial ischemia and reperfusion injury by targeting IGF-1. Oncotarget. 2016; 7, 39740–39757.Google Scholar
321. Lu, Y, Zhang, Y, Wang, N, et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010; 122, 2378–2387.Google Scholar
322. Du, W, Liang, H, Gao, X, et al. MicroRNA-328, a potential anti-fibrotic target in cardiac interstitial fibrosis. Cell Physiol Biochem. 2016; 39, 827–836.Google Scholar
323. Li, C, Li, X, Gao, X, et al. MicroRNA-328 as a regulator of cardiac hypertrophy. Int J Cardiol. 2014; 173, 268–276.Google Scholar
324. Ge, Y, Pan, S, Guan, D, et al. MicroRNA-350 induces pathological heart hypertrophy by repressing both p38 and JNK pathways. Biochim Biophys Acta. 2013; 1832, 1–10.Google Scholar
325. Garikipati, VN, Krishnamurthy, P, Verma, SK, et al. Negative regulation of miR-375 by interleukin-10 enhances bone marrow-derived progenitor cell-mediated myocardial repair and function after myocardial infarction. Stem Cells. 2015; 33, 3519–3529.Google Scholar
326. Ganesan, J, Ramanujam, D, Sassi, Y, et al. MiR-378 controls cardiac hypertrophy by combined repression of mitogen-activated protein kinase pathway factors. Circulation. 2013; 127, 2097–2106.Google Scholar
327. Yang, VK, Loughran, KA, Meola, DM, et al. Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a naturally occurring canine model. J Extracell Vesicles. 2017; 6, 1350088.Google Scholar
328. Liu, T, Zhong, S, Rao, F, Xue, Y, Qi, Z, Wu, S. Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients. Europace. 2016; 18, 92–99.Google Scholar
329. Tijsen, AJ, Creemers, EE, Moerland, PD, et al. MiR423-5p as a circulating biomarker for heart failure. Circ Res. 2010; 106, 1035–1039.Google Scholar
330. Ren, J, Zhang, J, Xu, N, et al. Signature of circulating microRNAs as potential biomarkers in vulnerable coronary artery disease. PLoS One. 2013; 8, e80738.Google Scholar
331. Song, L, Su, M, Wang, S, et al. MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1. J Cell Mol Med. 2014; 18, 2266–2274.Google Scholar
332. Xu, X, Li, H. Integrated microRNAgene analysis of coronary artery disease based on miRNA and gene expression profiles. Mol Med Rep. 2016; 13, 3063–3073.Google Scholar
333. Liu, H, Chen, GX, Liang, MY, et al. Atrial fibrillation alters the microRNA expression profiles of the left atria of patients with mitral stenosis. BMC Cardiovasc Disord. 2014; 14, 10.Google Scholar
334. Harling, L, Lambert, J, Ashrafian, H, Darzi, A, Gooderham, NJ, Athanasiou, T. Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation. Eur J Cardiothorac Surg. 2017; 51, 73–78.Google Scholar
335. Qiao, Y, Zhao, Y, Liu, Y, et al. miR-483-3p regulates hyperglycaemia-induced cardiomyocyte apoptosis in transgenic mice. Biochem Biophys Res Commun. 2016; 477, 541–547.Google Scholar
336. Wang, X, Zhang, X, Ren, XP, et al. MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury. Circulation. 2010; 122, 1308–1318.Google Scholar
337. Ling, TY, Wang, XL, Chai, Q, et al. Regulation of the SK3 channel by microRNA-499--potential role in atrial fibrillation. Heart Rhythm. 2013; 10, 1001–1009.Google Scholar
338. Adachi, T, Nakanishi, M, Otsuka, Y, et al. Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clin Chem. 2010; 56, 1183–1185.Google Scholar
339. Zhou, J, Shao, G, Chen, X, et al. miRNA 206 and miRNA 574-5p are highly expression in coronary artery disease. Biosci Rep. 2015; 36, e00295.Google Scholar
340. Weber, M, Baker, MB, Patel, RS, Quyyumi, AA, Bao, G, Searles, CD. MicroRNA expression profile in CAD patients and the impact of ACEI/ARB. Cardiol Res Pract. 2011; 2011, 532915.Google Scholar
341. Shan, H, Zhang, Y, Lu, Y, et al. Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines. Cardiovasc Res. 2009; 83, 465–472.Google Scholar
342. Zhang, JS, Zhao, Y, Lv, Y, et al. miR-873 suppresses H9C2 cardiomyocyte proliferation by targeting GLI1. Gene. 2017; 626, 426–432.Google Scholar
343. Wang, K, Liu, F, Liu, CY, et al. The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873. Cell Death Differ. 2016; 23, 1394–1405.Google Scholar
344. Liang, D, Xu, X, Deng, F, et al. miRNA-940 reduction contributes to human tetralogy of Fallot development. J Cell Mol Med. 2014; 18, 1830–1839.Google Scholar
345. Wang, K, Long, B, Li, N, et al. MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression. Free Radic Biol Med. 2016; 91, 58–67.Google Scholar
Figure 0

Fig. 1 Lifelong environmental challenges that alter heart functions. Numbers indicate the references of studies associating environmental challenges and cardiac alterations. ART, assisted reproductive technologies.

Figure 1

Table 1 Micro-RNAs associated to cardiac pathophysiology

Figure 2

Fig. 2 Micro-RNAs biogenesis. Micro-RNAs biogenesis involves different steps. Pri-micro-RNAs are transcribed from inter- and intra-genic regions. They are then processed into pre-micro-RNAs and double-stranded micro-RNAs. The mature single-stranded micro-RNAs binds to the UTR ends of targets messenger RNAs (mRNAs) to regulate their levels.