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.
Highlights
Many studies demonstrated that the shedding of the angiotensin-converting enzyme 2 (ACE2) catalytic ectodomain plays a role in the process of cardiac remodeling and endothelial dysfunction, it is unclear whether the presence of circulating soluble ACE2 in plasma indicates the cause or effect of an adaptive or maladaptive physiological process operating in heart failure (HF) and cardiovascular diseases
Notwithstanding, at the present time, it is proven by many studies that high soluble ACE2 plasma activity is a predictor of major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality [28,30,32,33,34,35,36]
A basic science study reported that endotoxins and the pro-inflammatory cytokines, interleukin-β (IL-1β) and TNFα, all enhanced soluble catalytic ectodomain ACE2 shedding from the airway epithelia, suggesting that soluble ACE2 plasma activity generation may have host defense functions [68]
Summary
On December 2019, at Wuhan, China had reported the first cases of pneumonia due to a novel coronavirus that was identified as a betacoronavirus in the same subgenus as the severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs) attachment [1].The. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses classified this this virus as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. SARS-CoV-1 attaches to the target cell through the interaction of the spike glycoprotein with its receptor, the angiotensin-converting enzyme 2 (ACE2) [6]. ACE2 binding triggers a spike protein-mediated fusion of the viral envelope with the cell plasma membrane or intracellular endosomal membranes. The laboratory findings of a higher neutrophil count, D-dimer, ferritin, c-reactive protein (CRP), and low lymphocyte count have been reported in severe COVID-19 and were associated with unfavorable prognosis [10,12,13]. Understanding the physiology of ACE2 could provide a better understanding of the cardiovascular disease and SARS-CoV-2 physiopathology
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