Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19

Abstract

An outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in Wuhan, China, at the end of 2019 has become a global pandemic. Both SARS-CoV-2 and SARS-CoV enter host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs. We have reviewed previously published studies on SARS and recent studies on SARS-CoV-2 infection, named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), confirming that many other organs besides the lungs are vulnerable to the virus. ACE2 catalyzes angiotensin II conversion to angiotensin-(1-7), and the ACE2/angiotensin-(1-7)/MAS axis counteracts the negative effects of the renin-angiotensin system (RAS), which plays important roles in maintaining the physiological and pathophysiological balance of the body. In addition to the direct viral effects and inflammatory and immune factors associated with COVID-19 pathogenesis, ACE2 downregulation and the imbalance between the RAS and ACE2/angiotensin-(1-7)/MAS after infection may also contribute to multiple organ injury in COVID-19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a potential target for developing specific drugs, antibodies, and vaccines. Restoring the balance between the RAS and ACE2/angiotensin-(1-7)/MAS may help attenuate organ injuries. SARS-CoV-2 enters lung cells via the ACE2 receptor. The cell-free and macrophage-phagocytosed virus can spread to other organs and infect ACE2-expressing cells at local sites, causing multi-organ injury.

Keywords: Angiotensin-converting enzyme 2; COVID-19; Multi-organ injury; SARS-CoV-2.

Fig. 1

The renin-angiotensin system (RAS) and ACE2/angiotensin-(1–7)/MAS axis. The protease renin converts angiotensinogen to Ang-I, which is subsequently converted to Ang-II by angiotensin-converting enzyme (ACE). Ang-II can bind to the angiotensin type 1 receptor (AT1R) to exert actions, such as vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress. ACE2 can covert Ang-I and Ang-II to angiotensin-(1–7). Angiotensin-(1–7) binds to the MAS receptor to exert actions of vasodilation, vascular protection, anti-fibrosis, anti-proliferation, and anti-inflammation. Ang-II can also bind to the angiotensin type 2 receptor (AT2R) to counteract the aforementioned effects mediated by AT1R

Fig. 2

A model for the process of SARS-CoV-2 entering host cells in the lungs and attacking other organs. SARS-CoV-2 enters the lungs, where the spike glycoprotein of the virus binds to ACE2 on cells, allowing the virus enter the cells. Some transmembrane proteinases, such as transmembrane protease serine 2 (TMPRSS2) and a disintegrin metallopeptidase domain 17 (ADAM17) also participate in this process. For example, SARS-CoV-2 can use TMPRSS2 for spike protein priming in cell lines. The infected cells and inflammatory cells stimulated by viral antigens can produce pro-inflammatory cytokines (PICs) and chemokines to activate immunological reactions and inflammatory responses to combat the viruses. Cell-free and macrophage-phagocytosed viruses in the blood can be transmitted to other organs and infect ACE2-expressing cells at local sites

Fig. 3

Main organs involved in COVID-19