title: Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart.
abstract: BACKGROUND
  A hallmark of aging of the cardiac myocyte is impaired sarcoplasmic reticulum (SR) calcium uptake and relaxation due to decreased SR calcium ATPase (SERCA) activity. We tested the hypothesis that H2O2-mediated oxidation of SERCA contributes to impaired myocyte relaxation in aging.
  
  
  RESULTS
  Young (5-month-old) and senescent (21-month-old) FVB wild-type (WT) or transgenic mice with myocyte-specific overexpression of catalase were studied. In senescent mice, myocyte-specific overexpression of catalase (1) prevented oxidative modification of SERCA as evidenced by sulfonation at Cys674, (2) preserved SERCA activity, (3) corrected impaired calcium handling and relaxation in isolated cardiac myocytes, and (4) prevented impaired left ventricular relaxation and diastolic dysfunction. Nitroxyl, which activates SERCA via S-glutathiolation at Cys674, failed to activate SERCA in freshly isolated ventricular myocytes from senescent mice. Finally, in adult rat ventricular myocytes in primary culture, adenoviral overexpression of SERCA in which Cys674 is mutated to serine partially preserved SERCA activity during exposure to H2O2.
  
  
  CONCLUSIONS
  Oxidative modification of SERCA at Cys674 contributes to decreased SERCA activity and impaired myocyte relaxation in the senescent heart. Strategies to decrease oxidant levels and/or protect target proteins such as SERCA may be of value to preserve diastolic function in the aging heart.
authors: Cardiovascular Medicine Section, Department of Medicine, The Myocardial Biology Unit and Vascular Biology Section, Boston University Medical Center, Boston, MA.
authors: Fuzhong
authors: F
authors: Qin
authors: Deborah A
authors: DA
authors: Siwik
authors: Steve
authors: S
authors: Lancel
authors: Jingmei
authors: J
authors: Zhang
authors: Gabriela M
authors: GM
authors: Kuster
authors: Ivan
authors: I
authors: Luptak
authors: Lei
authors: L
authors: Wang
authors: Xiaoyong
authors: X
authors: Tong
authors: Y James
authors: YJ
authors: Kang
authors: Richard A
authors: RA
authors: Cohen
authors: Wilson S
authors: WS
authors: Colucci
mesh_terms: D000367:Age Factors; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D003545:Cysteine; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D020536:Enzyme Activators; D016877:Oxidants; D006861:Hydrogen Peroxide; D002374:Catalase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D003545:Cysteine
keywords: aging; catalase; left ventricular diastolic dysfunction; oxidative stress
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