Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac...

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. The stimulator of interferon genes (STING) was highly expressed in human and mouse cardiac endothelial cells (ECs) and was activated at the onset of HF. Global and inducible EC-specific STING^-/- mice were used to demonstrate 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. ECs from EC-STING^-/- mice subjected to transverse aortic constriction were 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, STING activation induced IL-6 secretion. Furthermore, EC-derived IL-6 was 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.