To the Editor—Coronavirus disease 2019 (COVID-19), which affects type II alveolar cells of the human lung, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).^{Reference Zhu, Zhang and Wang1} This virus was identified in December 2019 in Wuhan, China, for the first time,^{Reference Lu, Stratton and Tang2} and has spread all over the world, leading to a global pandemic.^{Reference Whitworth3}

Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of COVID-19.^{Reference Del Rio and Malani4} The virus binds to its target cells through angiotensin-converting enzyme 2 (ACE2), which is found in the type II alveolar cells of the lungs. Furthermore, ACE2 receptors are expressed in many extrapulmonary tissues such as heart, kidney, testis, endothelia, and the gastrointestinal tract.^{Reference Lu, Zhao and Li5,Reference Wan, Shang, Graham, Baric and Li6} ACE2-expressing alveolar cells are also involved in the viral genome replication process.^{Reference Zhao, Zhao and Wang7}

ACE2 degrades angiotensin (ANG) I to angiotensin (1–9), which is a ligand for angiotensin II receptor type 2 (AT₂). ANG (1–9) has regenerative and anti-inflammatory effects through its binding to the AT₂ receptor.^{Reference Zambelli, Bellani and Borsa8} Moreover, ACE2 converts angiotensin II to angiotensin (1–7).^{Reference Donoghue, Hsieh and Baronas9} ANG (1–7), through binding to the Mas receptor (MasR), mediates anti-inflammatory and vasodilatory effects and reduces reactive oxygen species (ROS). Thus, it counteracts the vasoconstriction and proinflammatory effects of ANG II.^{Reference Tikellis and Thomas10,Reference Simões e Silva, Silveira, Ferreira and Teixeira11} In addition, ANG (1–7) may prevent lung injury because of its vasodilator effect.^{Reference Imai, Kuba and Rao12}

Importantly, SARS-CoV infections and SARS spike protein downregulate ACE2 expression.^{Reference Kuba, Imai and Rao13} Furthermore, blocking the RAS pathway deteriorated acute lung injury induced by the injection of SARS-CoV spike protein in mice. Thus, in contrast to most other coronaviruses, SARS-CoV may have become highly lethal because the virus dysregulates a lung protective pathway.^{Reference Reddy, Asante and Liu14}

Animal studies have shown that ACE2 protects murine lungs from acute lung injury as well as reconciles SARS spike protein lung injury, suggesting a dual role of ACE2 in both SARS infections and protection from ARDS.^{Reference Imai, Kuba and Rao12} The effect of ACE inhibitors (ACE-I) and angiotensin II type-I receptor blockers (ARBs) in the treatment and prevention of COVID-19 is not well recognized.

ACE-I and ARBs have been shown to upregulate the expression of ACE-2 or to prevent the loss of ACE2 in the heart; they may have a similar effect in lung tissue.^{Reference Ocaranza, Godoy and Jalil15,Reference Ferrario, Jessup and Chappell16} Thus, an ACE-I and ARB blocker prescription in COVID-19 patient may make the patient vulnerable due to additional virus entrance and replication in type II alveolar cells.

Hypertension, diabetes, and coronary heart disease were the most common comorbidities associated with death from COVID-19 in Wuhan patients,^{Reference Zhou, Yu and Du17} which leads us to 2 paradoxical hypotheses:

1. 1. The expression of ACE2 in hypertensive patients and patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors ARBs, is increased.^{Reference Li, Zhang and Zhuo18} This upregulation may make these patients more vulnerable.

2. 2. On the other hand, diabetes and hypertension are associated with decreased baseline levels of ACE2 expression.^{Reference Li, Zhang and Zhuo18} Therefore, SARS-CoV-2 binding to ACE2 may decrease residual ACE2 activity and lead to a predominance of ANG II through AT1 receptor signaling. In this case, ANG II causes pulmonary vasoconstriction and inflammatory and oxidative organ damage, ultimately progressing toward ARDS.^{Reference Zhang and Baker19}

Although some beneficial experimental evidence has emerged regarding ACEI or ARBs, and their use is well tolerated, inexpensive, and widespread; the potential therapeutic effects of these drugs in ARDS caused by SARS-CoV-2 is doubtful.

However, multiple regulatory associations have recommended that hypertensive COVID-19 patients do not stop taking their previosuly prescribed ACE inhibitors or ARBs.²⁰ The evidence offered here precedes any clinical trials, and the paradoxical role of the aforementioned drugs should be solved in preclinical and epidemiological studies.