A
model for how imbalance in the RAS pathway produces COVID-19 injury in
the heart
Figure 5 . Hypothesized model of cell-cell communication
in myocardial infection from SARS-CoV-2 and the influence of ACE1/ACE2
imbalance on a variety of cell types involved in cardiac injury.
By analogy with our model for lung injury from COVID-19 (Figure
3 ) and based on data in the literature, Figure 5 describes a
model for COVID-19 pathology in the heart. Below, we discuss details of
this model.
ACE2 is highly expressed in the myocardium in particular on cardiac
myocytes but also in endothelial cells and fibroblasts (Patel et al.,
2016; Santos et al., 2018). The binding of SARS-COV-2 to ACE2 from
Infection of the myocardium decreases ACE2 activity (Oudit et al., 2009)
and results in increased ACE1/ANG II driven signaling and a decrease in
effects of ACE2-derived peptides, including ANG (1-7). ANG II alters the
function of multiple cell types in the heart, including cardiomyocytes,
fibroblasts, endothelial cells and inflammatory cells, in particular
macrophages. ANG (1-7) action occurs on cardiomyocytes, inflammatory
cells and cardiac fibroblasts.
Akin to the lung, the heart has a local RAS that can contribute to
cardiac pathology (Dostal and Baker, 1999; De Mello and Danser, 2000;
Reyes et al., 2017; Forrester et al., 2018). ANG II has direct effects
on cardiomyocytes, increasing hypertrophy and contractility, altering
heart rate and rhythm, and enhancing secretion of cytokines that help
facilitate cardiac remodeling (Baker et al., 1992; Wen et al., 2012;
Reyes et al., 2017; Forrester et al., 2017). ANG II converts cardiac
fibroblasts to a more pro-fibrotic myofibroblast phenotype and enhances
secretion of factors (in particular TGF-β and RAS signaling components)
that promote hypertrophy via crosstalk with cardiomyocytes (Dostal and
Baker, 1999; Singh et al., 2008; Frieler and Mortensen, 2016; Forrester
et al., 2018). ANG II also exerts effects on endothelial cells, inducing
endothelial dysfunction and cytokine secretion, in particular of
endothelin-1, which enhances myocyte hypertrophy (Schmermund et al.,
1999; Forrester et al., 2018). RAS signaling can promote
pro-inflammatory effects on inflammatory cells, in particular cardiac
macrophages, which can further increase myocyte hypertrophy and
fibroblast activation (Frieler and Mortensen, 2016; Forrester et al.,
2018). ANG II signaling in multiple cardiac cell types increases
oxidative stress and reactive oxygen species (ROS) (Wen et al., 2012;
Kurdi and Booz, 2012; Forrester et al., 2018).
Signaling in the heart by ACE2-derived peptides, in particular ANG
(1-7), opposes effects of ANG II (Patel et al., 2016; Santos et al.,
2018). Via those actions, the ACE2- ANG (1-7)-MAS1 axis mitigates
hypertrophic, fibrotic, oxidative stress and remodeling effects of ANG
II. Protective effects via ACE2 on cardiac myocytes are likely
particularly important in cardiomyopathy and heart failure (e.g.,
Flores‐Muñoz et al., 2011).
ANG II thus alters multiple cell types in the heart and promotes a
pro-inflammatory, hypertrophic state via a range of mechanisms. These
mechanisms are counteracted by ACE2-derived products, in particular ANG
(1-7), implying an alteration in ACE1/ACE2 balance as a contributor to
the resultant cardiac phenotype. The SARS-CoV-2-promoted increase in
ACE1/ANG II actions resulting from a decrease in ACE2-derived peptides
is predicted to unleash inflammatory, oxidative stress and remodeling
events and potentially myocyte apoptosis, depressed myocardial function,
heart failure, arrythmia, and cardiac fibrosis.