SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: From basic science to clinical implications

Abstract

The current COVID-19 pandemic started several months ago and is still exponentially growing in most parts of the world - this is the most recent and alarming update. COVID-19 requires the collaboration of nearly 200 countries to curb the spread of SARS-CoV-2 while gaining time to explore and improve treatment options especially for cardiovascular disease (CVD) and immunocompromised patients, who appear to be at high-risk to die from cardiopulmonary failure. Currently unanswered questions are why elderly people, particularly those with pre-existing comorbidities seem to exhibit higher mortality rates after SARS-CoV-2 infection and whether intensive care becomes indispensable for these patients to prevent multi-organ failure and sudden death. To face these challenges, we here summarize the molecular insights into viral infection mechanisms and implications for cardiovascular disease. Since the infection starts in the upper respiratory system, first flu-like symptoms develop that spread throughout the body. The wide range of affected organs is presumably based on the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2). Physiologically, ACE2 degrades angiotensin II, the master regulator of the renin-angiotensin-aldosterone system (RAAS), thereby converting it into vasodilatory molecules, which have well-documented cardio-protective effects. Thus, RAAS inhibitors, which may increase the expression levels of ACE2, are commonly used for the treatment of hypertension and CVD. This, and the fact that SARS-CoV-2 hijacks ACE2 for cell-entry, have spurred controversial discussions on the role of ACE2 in COVID-19 patients. In this review, we highlight the state-of-the-art knowledge on SARS-CoV-2-dependent mechanisms and the potential interaction with ACE2 expression and cell surface localization. We aim to provide a list of potential treatment options and a better understanding of why CVD is a high risk factor for COVID-19 susceptibility and further discuss the acute as well as long-term cardiac consequences.

Keywords: ACE2; COVID-19; Cardiovascular disease; SARS-CoV-2.

Graphical abstract

Fig. 1

Overview about the role of ACE-2 during SARS CoV-2 infection. Angiotensin II can either bind to the angiotensin II receptor type I (AT₁-R), where it induces vasoconstriction via the phospholipase C (PLC), proteinkinase C (PKC) pathway, or be processed by angiotensin converting enzyme 2 (ACE2) to generate angiotensin 1–7. Afterwards, angiotensin 1–7 can bind to the MAS-receptor (Mas-R), which induces a signaling cascade subsequently leading to a vasodilatory effect. During SARS CoV-2 infection, viral spike protein (S) on the surface of the virus binds to ACE2. After processing of the S-protein by the endogenous transmembrane serine protease 2 (TMPRSS2), the viral particle is endocytosed and acidification of the endosome leads to viral and cellular membrane fusion and release of viral single-stranded RNA (ssRNA) into the cytosol. There, the ssRNA is replicated and translated into viral proteins (N, M, E and S). Additional viral mechanisms facilitate the downregulation of endogenous ACE2 and upregulation of ADAM metallopeptidase domain 17 (ADAM-17) expression. After vesicular transport to the cell surface, ADAM-17 facilitates its role as a “sheddase” and cleaves the extracellular domain of ACE2. Moreover, increased extracellular cytokine concentrations (TNFα, IFNγ, IL-4) lead to the activation of cellular proinflammatory pathways by different cytokine receptors. These pathways further support virus-induced downregulation of ACE2 and upregulation of ADAM-17.