Reply to Letter to the Editor: "COVID-19: is the ACE2 just a foe?"

to the editor: We would like to congratulate Dr. Hrvoje Jakovac for his valuable comments and thoughtful viewpoints and agree with all of them (2).

As one may learn from the title of our letter (1), the aim was to initiate a thoughtful discussion, underscoring the unknown and debated potential impact of contradictory mechanisms that operate through angiotensin-converting enzyme 2 (ACE2) on viral invasion and preservation of lung integrity during COVID-19 infection.

We appreciate Dr. Jakovac’s precise description of the significance of ACE2 and Ang-(1–7) in general and in general physiology and in the pathophysiology of lung injury in particular. Considering the important role of Ang-(1–7) in preserving lung integrity, the ideal therapeutic intervention for COVID-19 might be to selectively block the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attachment site on the ACE2 molecule while preserving the catalytic activity of ACE2. Alternatively, blocking ACE2 with potential pharmacological or immunological compounds that may reduce its affinity to SARS-CoV-2 may constitute a potential therapeutic approach, as long as Ang-(1–7) replacement therapy or a synthetic analogue is provided.

Concerning RAAS (renin-angiotensin-aldosterone system) blockers, we did not recommend the withdrawal of anti-RAAS medications, since as well pointed out, the evidence for detrimental effects is not fully established and needs to be weighed against the well-documented cardiovascular and kidney protective effects. Rather, we referred in our letter to the findings concerning the upregulation of tissue ACE2 in cardiovascular and metabolic diseases, especially in patients treated with RAAS blockers. That does not mean to stop these medications as is being done in many clinical settings, but rather to alert the clinical and research community to be aware of the potential for a transient and as yet not proven aggravating role these classes of medications may play in sensitizing some patients to SARS-CoV-2 complications.

In summary, our letter, in agreement with Dr. Jakovac’s thoughtful comments, suggests that any therapy based on ACE2 blockade for COVID 19 should be mindful of the need to guarantee the preservation of Ang-(1–7) availability either from endogenous or exogenous sources.

GRANTS

This work was supported in part by the Israel Science Foundation (Grants 544/18 and 182115) and the Kaylie Family Foundation.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Z.A.A., K.S., S.N.H., S.K., and Z.A. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.