Endothelial ActRIIA inhibition protects the cardiac microvasculature in severe viral respiratory infection

TL;DR

Blocking endothelial ActRIIA signaling protects the heart's blood vessels and improves survival in severe viral respiratory infections.

Contribution

Identifies endothelial ActRIIA as a novel therapeutic target for VRI-induced cardiac injury and proposes two pharmacological approaches.

Findings

Genetic deletion of EC ActRIIA reduces EC death and capillary loss in severe influenza.

ActRIIA inhibition improves myocardial perfusion, cardiac function, and survival in infected mice.

Two pharmacological strategies targeting EC ActRIIA show proof-of-concept therapeutic potential.

Abstract

Cardiac complications, including myocardial injury and dysfunction, are common in severe viral respiratory infections (VRI) and are associated with increased mortality
1–3
. The pathophysiology of VRI-induced myocardial injury is multifactorial, but frequently involves structural damage to the heart’s microvascular network that leads to subsequent myocardial ischemia and dysfunction
4–6
. Currently, there are no targeted therapies available to prevent or attenuate VRI-associated myocardial injury. Moreover, the molecular mechanisms driving the cardiac microvascular pathology in severe VRI are largely unclear. In this study, we identify increased endothelial cell (EC) activin type IIA receptor (ActRIIA) signaling as a key mediator of cardiac microvascular injury and pathologic remodeling in severe VRI. We show that genetic deletion of EC ActRIIA is sufficient to mitigate EC death and myocardial capillary loss in a murine model of severe influenza infection, which results in improved myocardial perfusion, cardiac function, and survival. We then provide proof-of-concept evidence for two novel pharmacological approaches to target EC ActRIIA pathophysiology in the treatment of VRI-induced cardiac dysfunction.