An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection

Abstract

It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled “ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome”), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients’ therapy.

A review of cytokine-based pathophysiology of Long COVID symptoms

“…Genetic polymorphism in the cytokine genes' regulatory regions can explain interindividual differences in the severity and symptoms of COVID-19. Different alleles of the cytokine genes affect the level and ratio of cytokines produced, altering the autoimmune and inflammatory response (233). ACE2 polymorphism is associated with susceptibility for SARS-CoV-2 infection and possibly the severity of disease (234, 235).…”

Vaccination for seasonal influenza, pneumococcal infection and SARS-CoV-2 in patients with solid tumors: recommendations of the Associazione Italiana di Oncologia Medica (AIOM)

“…SARS-CoV-2 infects human cells expressing the Angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease 2 (TMPRSS2). ACE2 is expressed throughout the body such as the epithelial cells of the oral mucosa, lungs, heart, gut and kidneys [ 86 ]. This explains the wide range of clinical manifestations of COVID-19 (i.e.…”

Unraveling the Underlying Molecular Mechanism of ‘Silent Hypoxia’ in COVID-19 Patients Suggests a Central Role for Angiotensin II Modulation of the AT1R-Hypoxia-Inducible Factor Signaling Pathway

“…The down-modulation of ACE2 following its interaction with Sarbecoviruses has been largely documented in vitro [ 76 , 77 ]. The control of ACE2 gene expression is a multifactorial and complex process that has been recently reviewed elsewhere [ 70 ]. The binding of SARS-CoV-2 spike S1 to ACE2 triggers an ACE2 ectodomain cleavage by the ADAM17 sheddase [ 78 , 79 , 80 ].…”

“…One can intuitively conceive that there is huge spatiotemporal heterogeneity in organ involvement in silent hypoxia, presumably due to the fact that certain organs are exposed in priority to SARS-CoV-2 infection and because multiple pathophysiological mechanisms may be causally involved in the early process of local hypoxia. The main cellular receptor to SARS-CoV-2, ACE2, is expressed in virtually all organs, with higher levels in organs that are richly vascularized, such as the lungs, heart, and kidneys [ 70 , 138 , 139 ]. In the upper airway, ACE2 expression is highest within regions of the sinonasal cavity and pulmonary alveoli and in the lung parenchyma [ 5 , 140 ].…”

“…Upon SARS-CoV-2 entry, the downregulation of ACE2 decreases its ability to generate angiotensin (1-9) from Ang I and angiotensin-(1-7) from Ang II, leading to renin–angiotensin system (RAS) imbalance and overactivation of the Ang II -AT1R axis. For more details, see reference [ 70 ].…”