Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure.

Capillary rarefaction and cardiomyocyte (CM) hypertrophy are hallmarks of the complex syndrome of heart failure (HF), a leading cause of hospitalization and death. Molecular signals within and between cellular components of the heart have emerged as central hubs that modulate cardiac pathophysiology. Here, we discovered that the stimulator of interferon genes (STING) is highly expressed in human and mouse cardiac endothelial cells (ECs) and is activated in the onset of HF. Using global and inducible EC-specific STING^-/- mice, we report that EC STING is required for contractile dysfunction in an experimental model of HF induced by transverse aortic constriction, through the regulation of CM hypertrophy and capillary rarefaction. We report that ECs sorted from transverse aortic constriction EC-STING^-/- mice are enriched in gene sets related to integrin and cell adhesion to extracellular matrix compared with controls. CellChat analysis of human cardiac cells from patients with nonischemic cardiomyopathy revealed EC-CM communication, and mechanistically, we found that STING activation induces IL-6 secretion. Furthermore, EC-derived IL-6 is necessary to induce prohypertrophic gene expression in CMs in a STING-dependent manner. The study demonstrates a novel role for STING in ECs, contributing to hypertrophy and contractile dysfunction in experimental HF.