To the Editor:
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly throughout the world. It has already posed a great threat to global public health security. Angiotensin-converting enzyme 2 (ACE2) has been identified as the major receptor of SARS-CoV-2. In addition, ACE2 is well-known as a counter-regulator of the renin-angiotensin system (RAS) and plays a key role in cardiovascular disease, especially hypertension. Thus, we are facing an important question: are patients with hypertension at increased risk of SARS-CoV-2 infection? The latest view from Fang et al. in The Lancet Respiratory Medicine1 was that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-I receptor blockers (ARBs) can result in the upregulation of ACE2, which may facilitate SARS-CoV-2 infection. They further suggested that antihypertensive calcium channel blockers (CCBs) can be a suitable alternative treatment for patients with hypertension or diabetes, because there is no evidence that CCBs can increase ACE2 expression or activity. Meanwhile, other literatures have also reported that patients who take ACEIs and ARBs may be at increased risk of severe disease outcomes due to SARS-CoV-2 infections2.
Here, we present a completely different perspective on the relationship between SARS-CoV-2 infection and ACEI/ARB drugs. Firstly, there is no sufficient evidence to support that ACEIs and ARBs can upregulate the protein level of ACE2 expression. Indeed, some studies have shown that the mRNA level of ACE2 can be increased by both ACEIs and ARBs, such as lisinopril (ACEI) and losartan (ARB)3. However, as we know, the change of protein levels is not always consistent with the mRNA levels, sometimes even in the opposite direction. So far, it is still inconclusive whether ACEIs and ARBs would increase ACE2 expression at the protein level. For example, ramipril (ACEI) was found to decrease ACE2 protein expression4. Besides, no changes in ACE2 protein expression was observed after the treatment of olmesartan (ARB)5. Therefore, there is no adequate evidence to support that ACEIs/ARBs increase the risk of the SARS-CoV-2 infection by up-regulating ACE2 protein level.
Secondly, ACE2 protein level is not completely related to the risk of SARS-CoV-2 infection. It is reported that ACE2 expression is higher in ileum than that in lung, but the ileum is not at higher risk of SARS-CoV-2 infection than the lung, suggesting other complicated mechanisms might be involved in virus infection. The possible mechanisms include other receptors, co-receptors or some unknown regulatory mechanism. Recently, angiotensin II type 2 receptor (AT2R), a G-protein coupled receptor, has been identified as one of the receptors for SARS-CoV-2, as well as the transmembrane glycoprotein CD1476,7. In addition, liver/lymph node-specific and dendritic cell-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN and DC-SIGN), which have been identified as the receptors of SARS-CoV8,9, are other potential receptors of SARS-CoV-2 as well. Thus, ACE2 expression is not the only factor affecting SARS-CoV-2 infection.
Thirdly, there is currently no evidence that ACEIs/ARBs increase the risk of SARS-CoV-2 infection based on clinical trials. For this question, it is impossible to give an answer through large-scale clinical trials within a relatively short time. From the perspective of target organ damage, if ACEIs/ARBs can increase the risk for SARS-CoV-2 infection, they will increase lung injury in patients. However, a study based on systematic review and meta-analysis of relevant clinical trials indicated that ACEIs reduced the risk of pneumonia and had a protective role, especially in patients with previous stroke and in Asia10. Although the evidence is not from patients with virus infection, the lung protective role of ACEIs is also inconsistent with the target organ damage of SARS-CoV-2 infection. Therefore, large-scale clinical trials are urgently needed to resolve this issue.
In summary, there is currently no clear evidence indicating that anti-RAS drugs (ACEIs and ARBs) increase the risk of SARS-CoV-2 infection, as well as target organ injury. There is still no need to recommend the discontinuation of ACEIs/ARBs for hypertensive patients with or at high risk of SARS-CoV-2 infection, or the change to other antihypertensive drugs.
Footnotes
Peer review under responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Acknowledgments
The authors acknowledge funding support from the National Natural Science Foundation of China (91939301, 81820108031, 91539123, and 81471893) and Beijing Municipal Natural Science Foundation (7172235, China).
Author contributions
All authors researched data for the article and discussed its content. Jingwei Bian wrote the manuscript. Rongsheng Zhao and Suodi Zhai discussed the content of manuscript and provided some advice. Zijian Li designed this manuscript, reviewed and edited it before submission.
Conflicts of interest
The authors declare no conflicts of interest.
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