Abstract Body: Introduction: Cardiomyocyte (CM) hypertrophy, endothelial cell (EC) dysfunction and cardiac inflammation are hallmarks of adverse cardiac remodeling that contribute to heart failure (HF) progression. The “Stimulator of Interferon Genes” (STING) is highly expressed in ECs, the dominant non-CM cell in the heart and contributes to vascular inflammation, yet its role in adverse cardiac remodeling is unknown. We hypothesized that EC STING contributes to systolic dysfunction by modulating adverse remodeling in HF.

Methods: Wildtype (WT), global deficient (STING-/-) and inducible EC STING-/- mice or
EC STING+/+ littermate controls (Cad5ERTCre2+/–Stingfl/fl treated with Tamoxifen or oil, respectively) were subjected to transverse aortic constriction (TAC) or Sham surgery for 2-8 weeks. Cardiac function was analyzed by echocardiography. Left ventricular (LV) sections were stained with wheat germ agglutinin and isolectin to analyze CM hypertrophy and capillary density. Cardiac leukocytes were analyzed by flow cytometry and gene expression by qPCR. Bulk RNA Sequencing was performed on sorted CD45- CD31+ mouse heart ECs (MHEC) from EC STING+/+ and EC STING-/- after 4 weeks of TAC or sham surgery. ELISA was performed on MHEC supernatant.

Results: STING-/- mice did not show a decline in fractional shortening (FS), capillary density or develop LV hypertrophy and had decreased intramyocardial CD45+ leukocytes in response to TAC, compared to WT mice. EC STING-/- mice also showed preserved FS, capillary density, and ameliorated CM hypertrophy over the course of 2, 4 and 8 weeks of TAC, compared to EC STING+/+ mice, despite having similar numbers of myocardial CD45+ leukocytes. RNASeq revealed decreased IL6 transcription, a pro-hypertrophic cytokine, in TAC STING-/- MHECs compared to WT MHECs. Myocardial IL6 gene expression was also reduced in EC STING-/- TAC hearts compared to EC STING+/+. In vitro, STING-/- MHECs had decreased secretion of IL6 protein compared to WT MHECs.

Conclusions: Our data demonstrate that EC STING modulates both the EC and cardiac expression of the pro-hypertrophic cytokine IL6, suggesting a mechanism contributing to cardiomyocyte hypertrophy, capillary rarefaction, and systolic dysfunction in response to cardiac pressure overload.