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:
  1. SARS viruses decrease ACE2 activity and expression.
  2. The decrease in ACE activity creates an imbalance in signaling by ACE1 and ACE2 products
  3. 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.
  4. 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.
  5. 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.