“Increased ACE 2 expression is a risk factor for SARS-CoV-2
infection”
ACE 2 expression has been detected for example in the heart, kidneys,
gastrointestinal tract (GIT), lungs, brain, testes, bladder, adipose
tissue, vascular system.5,8,14,15 Recently, ACE 2
expression was detected in cholangiocytes,16 in the
epithelial cells of the oral17 and nasal
mucosa.18 Various modes of
SARS-CoV-2 transmission
are possible due to the ubiquitous expression of ACE 2. The possibility
of infection through the GIT is discussed in the initial transmission
from an animal to humans.19 Intrapopulation
faecal-oral transmission is reported, especially in
children.20 Nonetheless, the droplet transmission
appears to be the most significant way for the intrapopulation
transmission.21
Respiratory tract
Why respiratory tract and
ARDS?
Zhao et al.22 analysed lung tissue of 8 human lung
donors and detected concentrated expression of ACE 2 RNA in a small
group of pulmonary cells. Most of them (83%) were type II alveolar
cells (AT 2). Surprisingly, only 1.4 % of the AT 2 expressed ACE 2 RNA,
and, compared to the AT 2 not expressing RNA ACE 2, this group expressed
other genes facilitating viral reproduction and transmission. The
SARS-CoV-2 spike
protein contains a sequence that can be cleaved into the S1 and S2
domains. Subsequent cleavage facilitates fusion of the virion into the
host cell.23,24 This cleavage may be performed via a
protease called furin 23 which is also used by other
respiratory viruses to penetrate into a host cell (but it is not
utilised e.g. by the original SARS-CoV),23,25 or by
transmembrane serine protease 2 (TMPRSS2).24 Both
proteases are significantly expressed in the respiratory
tract.25 So, it seems to be crucial that in addition
to the ACE 2 expression itself,
SARS-CoV-2 requires the
expression of further genes and activation of metabolic pathways for its
replication. This explains why lungs are the most vulnerable organ.
Smoking
Several studies documenting increased ACE 2 expression in smokers have
been published in relation to the current COVID-19 pandemics.
Immunohistochemistry analyses revealed higher expression of ACE 2
proteins in smokers as compared to non-smokers and increased ACE 2
expression in smokers with chronic obstruction pulmonary disease (COPD)
as compared to healthy smokers.26,27 Similarly to Zhao
et al.,22 ACE 2 was expressed in AT
2,26 in alveolar macrophages26 and
the small airway epithelium.26,27
Also studies28–30 based on transcriptome analyses
confirm the increased expression of RNA ACE 2 in lungs of smokers when
compared to non-smokers. Increased expression of ACE 2 RNA correlated
with the expression of genes included in the process of replication of
SARS-CoV-2.28,29Furthermore, there is a positive correlation between expression of ACE 2
RNA and the length and intensity of exposition to cigarette smoke in
mice.28 Higher ACE 2 expression in smokers seems to be
part of a complex change of metabolic processes facilitating the
replication of
SARS-CoV-2. Considering
the fact that smoking is a general risk factor for many respiratory
diseases31, including the Middle East Respiratory
Syndrome (MERS),32 smoking seems to be a clear risk
factor for incidence of COVID-19 infection.
It is therefore surprising that we do not have evidence significantly
showing epidemiological association between smoking and increased
incidence of SARS33 or COVID-19. Contrary to that,
Miyara et al.,34 for instance, compared the ratio of
smokers among 482 French patients with symptomatic COVID-19 with the
ratio of smokers in the general population and found out that smoking
seems to be a protective factor for development of symptomatic COVID-19.
Pharmacologically, they explained their results by nicotine-induced
reduction of ACE 2 expression.35 This hypothesis is
therefore contrary to studies where smoking increased ACE 2 protein
expression in pulmonary tissue in humans.26,27However, the level of ACE 2 expression in pulmonary tissue of patients
using nicotine patches compared to smokers would be of interest.
We have evidence of undetected patients infected with
SARS-CoV-2.36–38It is therefore possible that current data does not correspond to the
prevalence of
SARS-CoV-2 infection
among smokers compared to non-smokers in the general population, but
only to the ratio of smokers and non-smokers in severe cases. But,
studies analysing smoking as a risk factor worsening the course of
COVID-19 provide contradictory findings. There are studies showing
smoking as a risk factor for COVID-19 severity,39,40while other studies disprove the association between smoking and
COVID-19 severity.41,42 So, it will be extremely
interesting to wait for the results of larger epidemiological studies on
smoking, e.g. from Iceland colleagues who are testing a large part of
the population for the presence of
SARS-CoV-2.43,44
Other factors increasing the expression of ACE
2
The relationship between other factors and possible increase in ACE 2
expression in the respiratory tract is more ambiguous. Several
transcriptome analyses with non-coherent conclusions are available.
Cai30 did not detect a difference in ACE 2 RNA
expression between women and men, individuals younger and older than 60
years of age, or various ethnic groups, which contradicts the study of
Chen et al..45 Chen et al. found increased expression
of ACE 2 RNA in women, East Asian population and suggests negative
correlation between ACE 2 expression and age. Furthermore, he found
decreased expression of ACE 2 RNA in diabetic patients, contradicting
Pinto et al.,29 who found increased expression of ACE
2 RNA in patients with diabetes mellitus, hypertension and COPD. In
addition to the ambiguity, the possible discrepancy between RNA
expression and protein levels of ACE 246 is yet
another limiting factor of these analyses.
Benefit of reduced pulmonary ACE 2
expression?
With increased expression of ACE 2 being a risk factor for SARS-CoV-2
infection, a theoretical possibility to reduce the risk of SARS-CoV-2
infection appears to be ACE 2 blockage in the pulmonary tissue.
Inhibitor of ACE 2 was discovered in silico and it is supposed to
prevent the interaction between ACE 2 and SARS-CoV,47but the consequences of the inhibition of the generally protective ACE 2
have not been evaluated in vivo . Chloroquine and
hydroxychloroquine are used in the clinical practice wherein the
inhibition of the synthesis of sialic acids and the subsequent decrease
in ACE 2 glycosylation have been described as one of their mechanisms of
action in the treatment of COVID-19. Reduced ACE 2 glycosylation
decreases the affinity between SARS-CoV-2 and ACE 2.48
Tissues outside the respiratory
tract
Despite high ACE 2 expression, tissues outside the respiratory tissue
seem less significant for the pathogenesis of COVID-19. This may be
caused by the absence of further enzymes amplifying the replication
cycle of the SARS-CoV-2. However, extrapulmonary tissue cannot be
completely excluded from the pathogenesis of COVID-19. It is clearly
important for the initial contact between SARS-CoV-2 and the host with
the subsequent transfer of the virus into the pulmonary tissue.
Furthermore, there is evidence of the role of SARS-CoV-2 in the
pathogenesis outside the respiratory tract. The presence of SARS-CoV-2
and the subsequent tissue damage are suggested in
GIT,20,49 central nervous system
(CNS),50 kidneys51 and
liver.16 Decreased expression of ACE 2 on the surface
of platelets may contribute to the procoagulant
state.52 Similarly, SARS affected extrapulmonary
tissue, e.g. in a study analysing cardiac tissue of patients who
succumbed to SARS, virus was detected in 35% of patients, with
correlating downregulation of ACE 2 expression in cardiac
tissue.53
Pharmacological increase of ACE 2
expression
We hold evidence that some medication can increase the expression of ACE
2. Regrettably, there are no studies focusing on the pharmacological
modulation of ACE 2 expression specifically in the pulmonary tissue. The
influence of ACE-I and AT1 R blockers is a matter of intense
discussion.54–59 But, mineralcorticoid receptor
antagonists, statins, thiazolidinediones,59 ibuprofen,
as representatives of non-steroidal anti-inflammatory
drugs,60 are also associated with increased ACE 2
expression.
Recently published studies analysing the available evidence linking the
effect of ACE-I and AT1 R blockers to increased ACE 2 expression did not
demonstrate their clear and general effect on the increase of ACE 2
expression in humans.55,59 Furthermore, the different
effect of ACE-I and AT1 R blockers on ANG II concentration is also
discussed. While ACE-I, beta blockers or direct renin inhibitors
decrease the plasma concentration of ANG II, AT1 R increases the plasma
concentration of ANG II.58 Some
authors57 state that the increased concentration of
ANG II as a substrate for ACE 2 may lead to an increase in ACE 2
expression. On the other hand, ANG II has been shown to downregulate ACE
2 mRNA and protein expression levels in hypertensive
conditions.61 Therefore, some
authors58 warn of a possible upregulation in ACE 2
expression induced by beta blockers or direct renin inhibitors.
The extent of the possible increase in ACE 2 expression is also unknown.
There are data pointing to a fold increase in ACE 2 expression compared
to control groups,59 as well as studies where
pharmacotherapy significantly increased the expression of ACE 2, but by
far did not reach the level of the control
groups.60,62 It is clear that any suggestions to
changes in pharmacotherapy56 must be better supported
by experimental data. All the more so, as the data published so far have
not shown any negative association between drugs affecting the RAS
system and COVID-19.63–68