title: Role of Mitochondrial Oxidative Stress in Glucose Tolerance, Insulin Resistance, and Cardiac Diastolic Dysfunction.
abstract: Diabetes mellitus (DM) is associated with mitochondrial oxidative stress. We have shown that myocardial oxidative stress leads to diastolic dysfunction in a hypertensive mouse model. Therefore, we hypothesized that diabetes mellitus could cause diastolic dysfunction through mitochondrial oxidative stress and that a mitochondria-targeted antioxidant (MitoTEMPO) could prevent diastolic dysfunction in a diabetic mouse model.
  
  
  
  C57BL/6J mice were fed either 60 kcal % fat diet (high-fat diet [HFD]) or normal chow (control) for 8 weeks with or without concurrent MitoTEMPO administration, followed by in vivo assessment of diastolic function and ex vivo studies. HFD mice developed impaired glucose tolerance compared with the control (serum glucose=495±45 mg/dL versus 236±30 mg/dL at 60 minutes after intraperitoneal glucose injection, P<0.05). Myocardial tagged cardiac magnetic resonance imaging showed significantly reduced diastolic circumferential strain (Ecc) rate in the HFD mice compared with controls (5.0±0.3 1/s versus 7.4±0.5 1/s, P<0.05), indicating diastolic dysfunction in the HFD mice. Systolic function was comparable in both groups (left ventricular ejection fraction=66.4±1.4% versus 66.7±1.2%, P>0.05). MitoTEMPO-treated HFD mice showed significant reduction in mitochondria reactive oxygen species, S-glutathionylation of cardiac myosin binding protein C, and diastolic dysfunction, comparable to the control. The fasting insulin levels of MitoTEMPO-treated HFD mice were also comparable to the controls (P>0.05).
  
  
  
  MitoTEMPO treatment prevented insulin resistance and diastolic dysfunction, suggesting that mitochondrial oxidative stress may be involved in the pathophysiology of both conditions.
authors.affiliation: Cardiovascular Research Center, Lifespan Rhode Island Hospital, Providence, RI The Warren Alpert Medical School, Brown University, Providence, RI Providence Veterans Affairs Medical Center, Providence, RI.
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.affiliation: Section of Cardiology, University of Illinois at Chicago, IL.
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Chung
authors.affiliation: Cardiovascular Research Center, Lifespan Rhode Island Hospital, Providence, RI.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Warren Alpert Medical School, Brown University, Providence, RI.
authors.forename: Yeongju
authors.initials: Y
authors.lastname: Go
authors.affiliation: Section of Cardiology, University of Illinois at Chicago, IL.
authors.forename: Scott
authors.initials: S
authors.lastname: Gladstein
authors.affiliation: Section of Cardiology, University of Illinois at Chicago, IL.
authors.forename: Afshin
authors.initials: A
authors.lastname: Farzaneh-Far
authors.affiliation: Center for Cardiovascular Research, University of Illinois at Chicago, IL Department of Physiology and Biophysics, University of Illinois at Chicago, IL.
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.affiliation: Cardiovascular Research Center, Lifespan Rhode Island Hospital, Providence, RI The Warren Alpert Medical School, Brown University, Providence, RI Providence Veterans Affairs Medical Center, Providence, RI samuel_dudley@brown.edu.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003971:Diastole; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism*; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000378:metabolism*; D006439:Hemodynamics; D007333:Insulin Resistance; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005947:Glucose
keywords: diastolic dysfunction; insulin resistance; mitochondrial oxidative stress