title: Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload.
abstract: Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Siwik
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Andreia
authors.initials: A
authors.lastname: Biolo
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Vivian H
authors.initials: VH
authors.lastname: Tu
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: From the Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Massachusetts wilson.colucci@bmc.org.
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: H2O2; SERCA; apoptosis; catalase; hypertrophy