SARS viruses and Angiotensin signaling
Infection of cells by SARS viruses that bind ACE2 results in two
effects: inhibition of ACE2 activity and decrease of ACE2 expression in
infected cells (Kuba et al., 2005; Haga et al., 2008; Glowacka et al.,
2010; Dijkman et al., 2012; Zhang et al., 2020). Indirect evidence for
the latter response in COVID-19 is data showing elevation in circulating
ANG II with viral infection and increased circulating ANG II peptide
with higher viral loads (Liu et al., 2020b).
Our hypothesis is founded on the following ideas that derive from data
in reports cited in ensuing sections:
- SARS viruses decrease ACE2 activity and expression.
- The decrease in ACE activity creates an imbalance in signaling by ACE1
and ACE2 products
- This imbalance increases ANG II/AGTR1 signaling and is superimposed on
concurrent pathology (e.g., chronic lung disease, cardiac remodeling
in the lung and heart, respectively). ANG II is a pivotal mediator of
injury in both tissues; enhancement of its effects together with
signaling from comorbidities can increase severity of COVID-19.
- In patients more susceptible to the damaging effects of ANG II, the
decrease in ACE2 activity by SARS viruses can unleash a cascade of
injurious effects through a heightened imbalance in the actions of the
products of ACE1 versus ACE2.
- The proposed imbalance in the signaling and actions of products of
ACE1/ACE2 implies the potential of pharmacological approaches that
redress this imbalance via: a) decrease in ACE1 activity, b) blockade
of AGTR1, and/or c) increase in ACE2-mediated signaling by
affinity-trapping the SARs virus, enhancement of ACE2
expression/activity, or d) by agonists for receptors of ACE2-derived
peptides
We provide data from the literature in support of this hypothesis, in
particular as related to the lungs and the heart, and regarding
potential therapeutic approaches that address the imbalance of ACE1/ACE2
signaling and resultant actions involved in the pathobiology and
severity of COVID-19.