Abstract 12592: Nuclear Sirtuin Sirt6, Protects Mice From Endotoxin-Induced Septic Cardiomyopathy

Abstract

Introduction: Dysregulated systemic inflammatory response from host to infection can result in sepsis and multi-organ failure. Heart is one of the most affected organ. Even with recent medical advances, mortality rate with sepsis is 30-70%. Imbalance of inflammatory and metabolic pathways are crucial in the pathogenesis of sepsis and a multi-target approach is needed. SIRT6 is a key enzyme shown to restore energy homeostasis and to promote cardiac health in various adverse conditions. Hypothesis: We examined whether SIRT6 could alleviate pathogenic effects of sepsis in a murine lipopolysaccharide (LPS)-induced cardiomyopathy model. Methods: By injecting 10mg/kg LPS in wild-type (WT) and SIRT6 whole body overexpressing (T6-Tg) mice, endotoxemia was induced (n=5-6 each). Cardiac functions were assessed by echocardiography. Using heart tissues (n=3 each), TaqMan gene expression arrays were analyzed. Heart protein and serum cytokine levels were also estimated. Rat H9C2 cell line was used for in vitro studies. Results: SIRT6 overexpression in mice prevented LPS-induced hypothermia (p<0.001) and limited mortality to 30% compared to WT. LPS-injected T6-Tg mice showed preserved cardiac functions compared to WT (fractional shortening and ejection fraction, p<0.001). LPS-injected WT mice hearts showed 2- to 6-fold mRNA upregulation in pro-inflammatory transcription factors HIF1α, TLR4 and activating transcription factor 4 (ATF4). These factors were significantly (p<0.05) downregulated in LPS-injected T6-Tg hearts. With four-fold increase in ATF4 mRNA, a known inducer of amino acid transporters, expression of solute carriers (SLC3a2/7a1/7a5/7a8) was significantly upregulated in LPS-treated WT hearts, while reduced with SIRT6 overexpression. Pyruvate dehydrogenase kinase 4, which controls metabolic switch in sepsis, showed 4-fold increase in mRNA expression in LPS-treated H9C2 cells that was downregulated by SIRT6 overexpression. Similarly, upregulated inflammatory cytokines IL6, TNFα and lipocalin-2 were significantly (p<0.05) downregulated with SIRT6 overexpression. Conclusion: Our results indicate that SIRT6 could protect heart from LPS-induced sepsis by restoring metabolic homeostasis via regulation of multiple pathways.