“Decreased ACE 2 activity is a risk factor for
severity/lethality of
COVID-19”
The patient’s immune response seems to be the most important factor
influencing the course of COVID-19. SARS-CoV uses several strategies to
escape or suppress non-specific immune response. Comparison of patients
who succumbed to SARS with survivors showed that the development of an
adaptive immune response was a crucial factor. Specifically, the
synthesis of antibodies against the spike protein of
SARS-CoV.69 However, more detailed immunopathological
analysis is beyond the scope of this paper.
Decreased activity of ACE 2 in high-risk
comorbidities
Risk factors correlating positively with severity of COVID-19 have been
described as higher age, male sex, hypertension, diabetes and
cardiovascular diseases.70,71 Associations between
some of these factors and the change of ACE 2 expression/activity may be
found in the literature. Patients with heart failure have been reported
to have upregulated expression of both ACE 2 mRNA and protein in cardiac
tissue.72,73 However, there is also a study which
failed to find differences in the expression of ACE 2 protein in the
cardiac tissue between heart failure patients and healthy
individuals.5 In animal models, ACE 2 deficiency is
named as a risk factor worsening cardiac
pathogenesis.6,73 In patients with hypertension,
decreased vascular expression of ACE 2 may be expected, but ACE 2
activity in the CNS also plays an important role in the pathogenesis of
hypertension.6,73 Also diabetes mellitus is associated
with the reduction of ACE 2 activity 15,73. There are
studies reporting decreased expression of renal ACE 2 protein in
patients with diabetic nephropathy compared to healthy
control.74 On the other hand,
Lely
et al.75 failed to find difference in the renal
expression of ACE 2 protein in healthy individuals and patients with
renal damage, including diabetic nephropathy. A study in rats showed
correlation between higher age and decreased ACE 2 protein expression.
This decrease was more pronounced in males76. However,
there are studies which do not show any age-related changes of ACE 2
activity in rats77 and people78 with
ARDS. Non-coherent transcriptome analyses stated in the section 2.1.3 do
not provide a clear conclusion either.
Therefore, there are data supporting the theory that some risk factors
of COVID-19 severity correlate with lower baseline expression/activity
of ACE 2. And several authors are in favour of this
theory.52,79,80 On the other hand, the data not fully
compliant with this theory calls for caution. It is also important to
mention that several comorbidities, e.g. diabetes, older age, and
cardiovascular diseases, are negative prognostic factors in infectious
diseases with a different pathogenesis than that of
COVID-19 as
well.81
Benefit of increasing ACE 2
activity
In addition to the patient’s adaptive immune response, the survival of
COVID-19 requires maintained ACE 2 activity to avoid the development of
fatal ARDS, as stated above. During ARDS caused by SARS-Cov-2, ACE 2
activity in AT 2 is likely to be substantially reduced, and it is
therefore appropriate to restore it. The logical solution seems to be
the infusion of recombinant ACE 2 protein. In COVID-19, serum ACE 2
protein can bind circulating
SARS-CoV-2 and suppress
virus replication, in addition to reducing the unfavourable ANG II/ANG
(1-7) ratio. 19,82,83 From this point of view an
inhalation form of an ACE 2 analogue would be interesting because of
possible reduction of the viral load in the airways. The safety of
recombinant ACE 2 has been demonstrated in pilot clinical trials in
humans.8,19 It can therefore be expected for results
of valid clinical trials in patients with COVID-19 to be shown in the
near future.
Protective effect in ARDS may be expected from the administration of ANG
(1-7) as a product of ACE 2.84,85 A study wherein high
doses of calcitriol alleviated reduction of ACE 2 mRNA and protein
expression during acute lung injury in mice seems to also be of
interest.86 To provide a complete picture, calcitriol
itself has not significantly increased natural expression of ACE 2 mRNA
and protein in control group.
Some authors87,88 hypothesise a beneficial effect of
AT1 R blockers in the treatment of COVID-19 patients. They speculate
that AT1 R antagonism decreases harmful effects of ANG II. Furthermore,
increase of circulating ANG II as an ACE 2 substrate will lead to
quicker conversion to ANG (1-7). Consequently, Gurwitz assumes
upregulation of ACE 2 expression.88 There is evidence
supporting this hypothesis in ARDS conditions85 and
very limited population-based data associating treatment with AT1 R
blockers as a protective factor of COVID-19
severity.63,64 But clear and general effect of AT1 R
blockers on the increase in ACE 2 expression in humans is not
confirmed,55,59 as noted in section 2.2.1.
The currently available evidence supports the attempts to maintain ACE 2
activity in patients with severe COVID-19 as a life-saving strategy. It
also seems rational to avoid increasing ACE 2 activity by its expression
in the cells potentiating the replication cycle of
SARS-CoV-2, e.g. AT 2.
Further, a speculation on the use of direct ACE 2 activators: there have
been several studies supporting the use of 1-[[2-(dimethylamino)
ethyl] amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl) sulfonyl]
oxy] -9H-xanthone-9 (XNT) and diminazene aceturate (DIZE) in tissue
and animal models, where ACE 2 activation increased ANG (1-7) and
simultaneously decreased ANG II. 7,89 Unfortunately,
their toxicity is not known. Therefore, their introduction into the
clinical practice during the current COVID-19 pandemics is not
plausible, but they indicate a possible direction of development.