Journal Article

Enhanced Glycolytic Metabolism Contributes to Cardiac Dysfunction in Polymicrobial Sepsis

Ha, Tuanzhu, Liu, Li, Yu, Kaijiang, Wang, Xiaohui, Zheng, Zhibo, Zhang, Xia, Kao, Race, Fan, Min, Ma, He, Kalbfleisch, John, Williams, David, Xu, Jingjing, Tu, Fei, Wang, Ruitao, Li, Chuanfu

2017

Overview

Background. Cardiac dysfunction is present in >40% of sepsis patients and is associated with mortality rates of up to 70%. Recent evidence suggests that glycolytic metabolism plays a critical role in host defense and inflammation. Activation of Toll-like receptors on immune cells can enhance glycolytic metabolism. This study investigated whether modulation of glycolysis by inhibition of hexokinase will be beneficial to septic cardiomyopathy. Methods. Male C57B6/J mice were treated with a hexokinase inhibitor (2-deoxy-D-glucose [2-DG], 0.25–2 g/kg, n = 6–8) before cecal ligation and puncture (CLP) induced sepsis. Untreated septic mice served as control. Sham surgically operated mice treated with or without the 2-DG inhibitor served as sham controls. Cardiac function was assessed 6 hours after CLP sepsis by echocardiography. Serum was harvested for measurement of inflammatory cytokines and lactate. Results. Sepsis-induced cardiac dysfunction was significantly attenuated by administration of 2-DG. Ejection fraction and fractional shortening in 2-DG–treated septic mice were significantly (P < .05) greater than in untreated CLP mice. 2-DG administration also significantly improved survival outcome, reduced kidney and liver injury, attenuated sepsis-increased serum levels of tumor necrosis factor α and interleukin 1β as well as lactate, and enhanced the expression of Sirt1 and Sirt3 in the myocardium, which play an important role in mitochondrial function and metabolism. In addition, 2-DG administration suppresses sepsis-increased expression of apoptotic inducers Bak and Bax as well as JNK phosphorylation in the myocardium. Conclusions. Glycolytic metabolism plays an important role in mediating sepsis-induced septic cardiomyopathy. The mechanisms may involve regulation of inflammatory response and apoptotic signaling.

• Publisher: Oxford University Press
• Subject: Animals / Cardiomyopathies - metabolism / Cardiomyopathies - physiopathology / Cytokines - metabolism / Deoxyglucose - metabolism / Deoxyglucose - pharmacology / Deoxyglucose - therapeutic use / Disease Models, Animal / Glycolysis - drug effects / Glycolysis - physiology / Heart - drug effects / Heart - physiopathology / Hexokinase - antagonists & inhibitors / Hexokinase - metabolism / Lactic Acid - metabolism / Major / Male / Mice / Mice, Inbred C57BL / Myocardium - metabolism / PATHOGENESIS AND HOST RESPONSE / Sepsis - drug therapy / Sepsis - metabolism / Sepsis - mortality / Sepsis - physiopathology / Survival Analysis