Effect of depletion of Endothelial Cell STING in response to pressure overload induced 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 (EC) 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 (TAC), through the regulation of CM hypertrophy and capillary rarefaction. We report that ECs sorted from TAC EC-STING-/- mice are enriched in gene sets related to integrin and cell adhesion pathways to extracellular matrix (ECM) compared to controls and have decreased expression of the pro-hypertrophic gene IL-6. CellChat analysis of human cardiac cells from patients with non-ischemic cardiomyopathy revealed EC-CM communication, and mechanistically, we found that STING activation induces IL-6 secretion, and that EC derived IL-6 is necessary to induce pro-hypertrophic gene expression in CMs in a STING dependent manner. Our study demonstrates a novel role for STING in ECs contributing to hypertrophy and contractile dysfunction in experimental HF. Overall design: RNA-seq profiling of CD45- CD31+ Endothelial Cells flow cytommetry sorted out from murine hearts of Cad5CreERT2+/+STINGfl/fl and Cad5CreERT2-/-STINGfl/fl mice subjected to 4 weeks of transverse aortic constriction (TAC) or sham surgery.