Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19

Abstract

The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that exists in two forms: the first is a transmembrane protein; the second is a soluble catalytic ectodomain of ACE2. The catalytic ectodomain of ACE2 undergoes shedding by a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), in which calmodulin mediates the calcium signaling pathway that is involved in ACE2 release, resulting in a soluble catalytic ectodomain of ACE2 that can be measured as soluble ACE2 plasma activity. The shedding of the ACE2 catalytic ectodomain plays a role in cardiac remodeling and endothelial dysfunction and is a predictor of all-cause mortality, including cardiovascular mortality. Moreover, considerable evidence supports that the ACE2 catalytic ectodomain is an essential entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Additionally, endotoxins and the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-alpha (TNFα) all enhanced soluble catalytic ectodomain ACE2 shedding from the airway epithelia, suggesting that the shedding of ACE2 may represent a mechanism by which viral entry and infection may be controlled such as some types of betacoronavirus. In this regard, ACE2 plays an important role in inflammation and thrombotic response, and its down-regulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury. Soluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. Furthermore, given that vitamin D enhanced the shedding of ACE2, some studies reported that vitamin D treatment is associated with prognosis improvement in COVID-19. This is an updated review on the evidence, clinical, and therapeutic applications of ACE2 for COVID-19.

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19

“…have shown that sACE is promoting rather than inhibiting the entry of the virus in the cells suggesting a proviral role of sACE2 increasing the virus entry ( 34 ). However, in agreement with our other reports it have been shown that sACE2 blocks, rather than enhance, the pseudotyped infection in cell cultures or even SARS-CoV2 infection in cell cultures and animal models ( 35 – 39 ). The reasons of the possible discrepancies are unknown but could be related to that the pro-infection effect of sACE2 could be relevant in cells/tissues where TMPRSS is not expressed or the different sources of rsACE2 used.…”

“…More importantly, hsACE2 was able to strongly inhibit in vivo (over 90%) SARS-CoV-2 pseudovirus infection and the serum concentrations extrapolated by them ( 40 ) were similar than those described here and presented in our sera. Checking the protective effect of ACE2 would support the utility of soluble ACE2 as a therapy Our results are consistent with the recent results that support use of serum ACE2 as therapy [reviewed in ( 39 )] and clinical trials are underway for rhACE2 ( 41 ).…”

The role of angiotensin-converting enzyme 2 (ACE2) genetic variations in COVID-19 infection: a literature review

“…Kornilov and colleagues have observed that COVID-19-related regulatory pathways may induce ACE2 shedding, and the sACE2 concentrations may correlate with the level of systemic inflammation associated with COVID-19 [ 42 ]. Furthermore, the calmodulin–calcium signaling pathway which contributes to ACE2 release has been suggested to add new insights for clinical/therapeutic applications of ACE2 for COVID-19 [ 43 ].…”

Mechanisms of Cardiovascular System Injury Induced by COVID-19 in Elderly Patients With Cardiovascular History

“…Angiotensin-converting enzyme 2, a type I integral membrane protein, acts as a transmembrane protein or a soluble catalytic ectodomain in vivo ( 12 ). The transmembrane ACE2 can be measured as ACE2 expression, and studies indicate that the transmembrane ACE2 is abundant in lungs, heart, and endothelial cells (ECs) ( 13 , 14 ).…”

“…A disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) mediates cleavage and shedding of the soluble ACE2 ectodomain. ACE2 ectodomain, also known as soluble ACE2, can be detected as plasma ACE2 activity ( 12 ). The soluble ACE2 has been recently recognized to help in controlling SARS-CoV-2 infection via inhibiting their interaction with cell-bound ACE2 ( 17 ).…”