Potential detrimental role of soluble ACE2 in severe COVID‐19 comorbid patients

Abstract

Summary Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) enters the host cell by binding to angiotensin‐converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain‐containing protein 17 (ADAM17) also known as tumour necrosis factor‐α‐converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1–7), to balance the renin angiotensin system. Membrane‐bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS‐CoV‐2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non‐primed virus–sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II‐angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.

Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS)

“…The therapeutic value of sACE2 has been suggested to exert a dual effect; a reduction in the levels of the vasoconstrictor angiotensin II, and blocking viral entry by masking the spike protein. However, in our cohort, as in other studies, severely ill patients, despite having high sACE2 levels, did not seem to gain a benefit in viral infection [34]. It has been proposed that a possible detrimental role of high sACE2 could be due to the binding of the virus to many sACE2 molecules; the virus-sACE2 complex can spread the virus to distant organs and create sACE2 and membrane ACE2 depletion.…”

“…It has been proposed that a possible detrimental role of high sACE2 could be due to the binding of the virus to many sACE2 molecules; the virus-sACE2 complex can spread the virus to distant organs and create sACE2 and membrane ACE2 depletion. The resulting increased angiotensin II, part of the bigger pathology, might aggravate the disease [34]. It is thus of utmost importance to monitor both sACE2 and angiotensin II levels in COVID-19 patients to ensure the safe and efficient use of therapeutic sACE2.…”

A Dual-Route Perspective of SARS-CoV-2 Infection: Lung- vs. Gut-specific Effects of ACE-2 Deficiency

“…The sACE-2 is derived by shedding from the membranes due to the hydrolyzing activity of a membrane-anchored metalloproteinase 17 (ADAM17; Patel et al, 2014). ADAM17, involved in proinflammatory processes in epithelial and endothelial cells, is increased in several pathologies, including cardiopulmonary, and renal systems and gastrointestinal inflammatory diseases such as ulcerative colitis (Rahman et al, 2021). ACE-2 deficiency due to SARS-CoV-2 binding to the ACE-2 receptor, activates ADAM-17 (Andring et al, 2020).…”

“…However, this soluble sACE-2 could act as a decoy to bind the virus and decrease the likelihood of viral binding to membrane-bound ACE-2. It has been recently suggested that the sACE-2 retains catalytic activity and that the sACE-2-virus complex could interact with TMPRSS2 and thus contribute to infection (Rahman et al, 2021). Increased sACE2 activity was observed in patients with heart failure (Epelman et al, 2008).…”

Defective efferocytosis as a predictor of COVID-19 mortality

“…However, the plasma RAS balance in COVID-19 patients was already characterized by a strong transient increase in circulating plasma sACE2 [66]. Therefore, in COVID-19 patients with comorbid diseases, both Angiotensin II and virus adversely affect the prognosis by affecting the RAS balance in a way that down-regulates ACE2 [96]. Interestingly, recent study reports encouraging results in the first severe COVID-19 patient treated with hrsACE2 [97].…”