Abstract 15505: Cardiac-Specific Jarid2 Deficiency, Results in Improved Survival and Myocardial Function Following Experimental Sepsis

Introduction: Myocardial depression and associated hemodynamic collapse are among the major causes of death in severe sepsis. Management of severe sepsis is largely supportive. Hypothesis: Emerging evidence suggests that the transcriptional repressor Jarid2 may play a regulatory role in sepsis; however, the functional role of Jarid2 in sepsis-induced myocardial dysfunction remains uninvestigated. Methods: Using both in in vivo (murine model of cecum ligation and puncture (CLP) in 12-week-old C57-wild type (WT) and cardiac specific Jarid2(knock-out, KO)) and in vitro (lipopolysaccharide, LPS) treatment of cultured murine cardiac myocytes) approaches we determined whether Jarid2 is a putative novel target for sepsis. Results: In response to CLP for 48hrs, WT displayed >60% mortality, survivors developed bacterial peritonitis, a marked inflammatory response (3-5-fold increases in serum and left ventricular (LV) interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha), myocardial dysfunction (20-35% decreases in dp/dt and echo-derived % ejection fraction (EF) and % fractional shortening (FS)), and a 40-50% decrease in LV Jarid2mRNA and protein compared to WT-sham. Jarid2KO mice showed resistance to CLP-induced bacterial peritonitis resulting in improved cardiac function (10-15% decrease in %EF and %FS), and survival (>90%) despite an exacerbated (10-15-fold increase in LV) inflammatory response compared to WT mice. In adult cultured cardiac myocytes derived from WT and Jarid2KO mice, treatment with the endotoxin LPS (1 microgram/mL) for 24 hrs, resulted in an 8-10-fold and 20-35-fold increase respectively, in the inflammatory cytokines TNF-alpha, IL-1beta and IL-6. Conclusions: These findings reveal that the loss of Jarid2 enhances bacterial clearance and despite an enhanced inflammatory response, resulted in improved myocardial function and survival following CLP-induced sepsis. As such, Jarid2 may be a novel therapeutic target in the treatment of sepsis-induced myocardial dysfunction.