Abstract 354: Sirt1 Negatively Regulates Cardiac Inflammation Induced by Metabolic Stress

Abstract

Obesity is a major risk factor for heart disease. Metaflammation is a metabolically driven, chronic, low-grade inflammatory reaction that is seen in the heart under obese conditions. Cardiac myocytes are known to produce inflammatory cytokines such as interleukin-6 (IL-6). However, whether and how cardiac myocytes mediate metaflammation is unknown. Silent information regulator 1 (Sirt1), a histone deacetylase involved in numerous metabolic pathways, facilitates an anti-inflammatory function through inhibition and deacetylation of the NFkB p65 subunit. This project aims to examine whether Sirt1 plays a role in cardiac local metaflammation. Mice with cardiac specific Sirt1 gene deletion (c-Sirt1 KO), Sirt1 overexpression (Tg-Sirt1), and relevant controls (Flox/Flox and WT respectively) were each placed on high fat and regular chow diets. The mice were euthanized after 3 months and their hearts were extracted for genetic and molecular analyses. Sirt1 mRNA and protein levels were significantly decreased under HFD feeding conditions (50% reduction in HFD feeding compared to normal diet, P<0.05). Acetylation of p65 was significantly induced by HFD feeding, and was further enhanced in c-Sirt1 KO mice, but inhibited in Tg-Sirt1 mice. Cardiac inflammation was enhanced in the c-Sirt1 KO group as evidenced by a significant increase in mRNA levels of IL-6 in mice fed regular chow (3-fold increase in c-Sirt1 KO vs. Sirt1 Flox/Flox, p<0.05) and HFD (5-fold increase in c-Sirt1 KO vs. Sirt1 Flox/Flox, p<0.05). Intracellular IL-6 signaling steps, such as phosphorylation of STAT3, were enhanced in c-Sirt1 KO, but inhibited in Tg-Sirt1 mice under HFD feeding conditions. These results suggest that cardiac myocytes mediate metaflammation partly through downregulation of Sirt1.