Abstract P3078: The Stimulator Of Interferon Genes (STING) Modulates Adverse Cardiac Remodeling Induced By Cardiac Pressure Overload: New Role Of Endothelial Cell Sting In Systolic Dysfunction

Abstract

Introduction: Cardiac inflammation is a hallmark of heart failure (HF) defined by T cell infiltration and increased expression of pro-inflammatory cytokines. Type I Interferon (IFN-I), a cytokine induced upon activation of STING, is increased in the heart after myocardial infarction and transverse aortic constriction (TAC). We reported that absence of endothelial cell (EC) STING results in an IFN-I dependent decline in T cell extravasation to inflammatory sites. We hypothesized that STING contributes to adverse cardiac remodeling induced by TAC and EC STING regulates systolic dysfunction through modulating cardiac inflammation. Methods: Male wildtype (WT), STING -/- and inducible EC specific STING -/- mice (Cad5 ERTCre2+/- STING fl/fl treated i.p. with 85mg/kg Tamoxifen), or oil treated and Cre - littermate WT controls were subjected to TAC or Sham surgery. Systolic function by echocardiography and left ventricular (LV) hypertrophy, fibrosis, and capillary density by histology were analyzed four weeks post-surgery and T cell activation was characterized in mediastinal draining lymph nodes (MdLN) by flow cytometry. Results: In contrast to WT, STING -/- mice did not show a decline in ejection fraction (EF). LV hypertrophy was decreased in TAC STING -/- mice compared to TAC WT mice. Isolectin staining showed that capillary density was higher in STING -/- mice in response to TAC as compared to the expected capillary loss observed in WT TAC mice. The frequency of CD4+CD62 lo CD44 hi cells in the MdLN, indicative of effector T cell activation, was decreased in STING -/- mice compared to WT mice in response to TAC. Similar analyses of Cad5 ERTCre2+/- STING fl/fl mice showed that EC STING -/- mice did not show a decline in EF in response to TAC, in contrast to their littermate WT controls. However, no changes were observed in LV hypertrophy, fibrosis or capillary density between groups and activation of MdLN effector T cells was also comparable in both groups. Conclusion: STING contributes to adverse cardiac remodeling induced by TAC. While EC STING contributes to systolic dysfunction through a yet unknown mechanism, STING in other cell compartments contributes to cardiac hypertrophy, capillary density and T cell activation in response to TAC.