title: Enhanced Glycolytic Metabolism Contributes to Cardiac Dysfunction in Polymicrobial Sepsis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Glycolytic metabolism plays an important role in mediating sepsis-induced septic cardiomyopathy. The mechanisms may involve regulation of inflammatory response and apoptotic signaling.
authors.affiliation: Departments of Surgery.|Biometry and Medical Computing, and.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Departments of Surgery.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: He
authors.initials: H
authors.lastname: Ma
authors.affiliation: Departments of Surgery.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Surgery.
authors.forename: Fei
authors.initials: F
authors.lastname: Tu
authors.affiliation: Departments of Surgery.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Surgery.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.affiliation: Departments of Surgery.
authors.forename: Min
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, and.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Departments of Surgery.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine and Intensive Care Unit, Harbin Medical University Cancer Hospital,Heilonjiang,China.
authors.forename: Kaijiang
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine and Intensive Care Unit, Harbin Medical University Cancer Hospital,Heilonjiang,China.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Wang
authors.affiliation: Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.affiliation: Departments of Surgery.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: Race
authors.initials: R
authors.lastname: Kao
authors.affiliation: Departments of Surgery.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Departments of Surgery.|Department of Nephrology, BenQ Medical Center, Nanjing Medical University, and.
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D019344:Lactic Acid; D003847:Deoxyglucose; D006593:Hexokinase; C000598049:hexokinase 2, mouse
keywords: 2-deoxy-D-glucose; cardiomyopathy; glycolysis; inflammatory responses.; sepsis