Introduction

COVID-19 (corona virus disease 2019) is a designation issued by the World Health Organization (WHO) on February 11, 2020 for the disease caused by SARS-CoV-2 coronavirus (severe acute respiratory syndrome-related coronavirus). The first cases appeared in December 2019 in the Chinese city of Wu-Chan, Hubei province, and the disease gradually spread to most countries all over the world.1
SARS-CoV-2 bears many similarities to the already known beta-coronavirus SARS-CoV.2,3 SARS-CoV is the cause of SARS, which broke out in Guangdong Province, China in 2002.4 In addition to their common phylogenetic origin in bats,3(p2) both viruses demonstrate an identical mechanism of entry into a host cell. Their entry receptor is the angiotensin-converting enzyme 2 (ACE 2) and the virion bond to ACE 2 is mediated by the spike protein of the virion envelope.2,3 SARS-CoV and SARS-CoV-2 spike proteins shares about 76% concordance in amino acid sequences and nearly identical 3D structure.2 SARS-CoV and SARS-CoV-2 do not use aminopeptidase N or dipeptidyl peptidase 4 as an entry receptor, contrary to some other coronaviruses.3

Role of ACE 2 in homeostasis

ACE 2, a homologue of the much better known angiotensin-converting enzyme, was discovered in 2000.5 This discovery, together with the newly discovered angiotensin (ANG) (1-7) and theMas receptor, revealed another branch of the renin-angiotensin system (RAS)6,7 (see Figure 1) Schematic of the renin-angiontensin system . Both ACE 2 and its ACE isoform are carboxypeptidases cleaving amino acids from the carboxyl end of the peptide. However, the difference in their enzymatic selectivity is crucial. While ACE cleaves 2 amino acids from ANG I decapeptide, producing an ANG II octapeptide, ACE 2 cleaves 1 amino acid from ANG I to form ANG (1-9). ACE converts ANG (1-9) to ANG (1-7). ANG II is analogously converted by ACE 2 to ANG (1-7).6,7 ACE 2 activity is not inhibited by ACE inhibitors (ACE-I).5
ANG (1-7) is a ligand for the Mas receptor and seems to be the principal peptide of the ACE 2/ANG (1-7)/Mas branch of the RAS system. In general, the ACE 2/ANG (1-7)/Mas branch counteracts vasoconstriction, sodium retention, proliferation/hypertrophy, fibrosis, oxidative stress, and arrhythmogenesis caused by the ACE/ANG II/angiotensin receptor 1 (AT1 R) cascade.6–8

Role of ACE 2 in SARS/COVID-19

ACE 2 was identified as a functional receptor for SARS-CoV in vitro 9 and in vivo 10. SARS-CoV replication was significantly lower in the group of ACE 2 knockout mice compared to the control group of wild-type mice.10 Analogously, higher rate of SARS-CoV replication was demonstrated in the group of transgenic mice for human ACE 2 (with overexpressed ACE 2) compared to the control group of wild-type mice.11 Thus, there is a positive correlation between the level of ACE 2 expression and the rate of SARS-CoV replication.
ACE 2 acts not only as the entry receptor for SARS-CoV, but its expression is also downregulated during SARS. It was proved in vivo , that reduction of ACE 2 expression is cause directly by interaction between SARS-CoV spike protein and ACE 2 protein.10 Due to similarity between SARS-CoV and SARS-CoV-22,3we may expect similar pathogenesis in COVID-19.
Reduction of ACE 2 activity leads to increased ANG II concentration and decreased ANG (1-7) concentration. The increased ANG II/ANG (1-7) ratio leads to the acute respiratory distress syndrome (ARDS).12,13 Therefore, the reduction of ACE 2 activity with consequent RAS imbalance seems to be an essential factor contributing to the lethality of SARS/COVID-19.10
The above stated, seemingly contradictory roles of ACE 2 in the pathogenesis of COVID-19 point to the following consequences:
1.      Increased ACE 2 expression is a risk factor for SARS-CoV-2 infection and the rate of COVID-19 development in the early phase of the disease. 2.    Decreased ACE 2 activity (or more specifically increased ANG II / ANG (1-7) ratio) is a risk factor for severity/lethality of COVID-19.