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.