Abstract 4140244: In a Murine Model of Experimental Sepsis, Cardiac-Specific Jarid2 Knockdown is Associated With Improved Myocardial Function and Survival

Introduction: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to acute heart failure, decreased contractile function, and biventricular dilation. Emerging evidence suggests that the transcriptional repressor Jarid2 may play a regulatory role in sepsis. Hypothesis: We hypothesize that cardiac-specific knockdown (KD) of Jarid2 could enhance cardiac function and improve survival in response to sepsis. Methods: We generated mice with cardiac-specific Jarid2KD using an alpha myosin heavy chain-specific Cre-LoxP system. Using an in vivo model of cecal ligation and puncture (CLP) with 12-week-old wild-type (WT) and cardiac-specific Jarid2KD mice we investigated whether Jarid2 is a potential novel target for sepsis treatment. Results: In response to 48 hours of CLP, WT mice exhibited over 60% mortality vs. WT-Sham. Survivors developed bacterial peritonitis, an increased inflammatory response (left ventricle (LV): 15-fold increase in IL-6, 3-fold increase in IL-1β and TNF-α, vs. WT-Sham), and apoptosis (LV: 2.5-fold increase in apoptotic Bax/Bcl2 ratio vs. WT-Sham). Jarid2KD showed myocardial dysfunction with a 20-35% decrease in dp/dt, echo-derived ejection fraction (EF), fractional shortening (FS)), a switch from adult α-myosin heavy chain (MHC) to fetal β-MHC, and a 40-50% reduction in LV Jarid2 mRNA and protein compared to WT-Sham. In contrast, Jarid2KD mice despite a similar decrease in LV Jarid2 expression to WT-CLP mice, demonstrated resistance to CLP-induced bacterial peritonitis with cardiac function (dp/dt, EF, FS) similar to the WT-Sham. Histological staining revealed better organization of cardiomyocytes and preservation of functional ultrastructure. Furthermore, Jairid2KD displayed a survival rate of over 90%, a reduced LV inflammatory response (LV: 2-fold increase in IL-6, no change in IL-1β and TNF-α), maintenance of α-MHC, and absence of apoptosis vs. WT-CLP. Metabolic genes such as NDUFA9, Cox4il, ND1, ND4 and PGC1b were downregulated approximately 60-75 per cent in Jarid2KD vs WT-CLP suggesting an improved ability to regulate energy usage. Improved survival was observed even 7 days post-CLP (65% in WT-CLP compared to 100% in Jarid2KD). Conclusion: Cardiac-specific JARID2KD improves survival and reduces sepsis-induced myocardial dysfunction. Thus, Jarid2 may serve as a novel therapeutic target for treating sepsis-induced myocardial dysfunction.