title: Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits.
abstract: Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase activity and endoplasmic reticulum (ER) stress are increased after myocardial infarction (MI). In this study, we proposed to test whether activation of the NADPH oxidase in the remote non-infarcted myocardium mediates ER stress and left ventricular (LV) remodeling after MI. Rabbits with MI or sham operation were randomly assigned to orally receive an NADPH oxidase inhibitor apocynin or placebo for 30 days. The agents were administered beginning at 1 week after surgery. MI rabbits exhibited decreases in LV fractional shortening, LV ejection fraction and the first derivative of the LV pressure rise, which were abolished by apocynin treatment. NADPH oxidase Nox2 protein and mRNA expressions were increased in the remote non-infarcted myocardium after MI. Immunolabeling further revealed that Nox2 was increased in cardiac myocytes in the remote myocardium. The apocynin treatment prevented increases in the Nox2 expression, NADPH oxidase activity, oxidative stress, myocyte apoptosis and GRP78, CHOP and cleaved caspase 12 protein expression in the remote myocardium. The apocynin treatment also attenuated increases in myocyte diameter and cardiac fibrosis. In cultured H9C2 cardiomyocytes exposed to angiotensin II, an important stimulus for post-MI remodeling, Nox2 knockdown with siRNA significantly inhibited angiotensin II-induced NADPH oxidase activation, reactive oxygen species and GRP78 and CHOP protein expression. We conclude that NADPH oxidase inhibition attenuates increased ER stress in the remote non-infarcted myocardium and LV remodeling late after MI in rabbits. These findings suggest that the activation of NADPH oxidase in the remote non-infarcted myocardium mediates increased ER stress, contributing to myocyte apoptosis and LV remodeling after MI.
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China.
authors.forename: Bao
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China; Department of Medicine and Central Laboratory, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China; Department of Medicine and Central Laboratory, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China.
authors.forename: Tao-Rui
authors.initials: TR
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China; Department of Medicine and Central Laboratory, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
authors.forename: Rui-Fang
authors.initials: RF
authors.lastname: Chi
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China.
authors.forename: Xin-Ling
authors.initials: XL
authors.lastname: Hu
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China.
authors.forename: Yue-An
authors.initials: YA
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, The Affiliated Cardiovascular Disease Hospital of Shanxi Medical University, Taiyuan 030024, Shanxi, PR China; Shanxi Province Cardiovascular Disease Institute, Taiyuan 030024, Shanxi, PR China; Department of Medicine and Central Laboratory, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China. Electronic address: sxcvh13@sina.com.
authors.forename: Fu-Zhong
authors.initials: FZ
authors.lastname: Qin
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
authors.forename: Wei-Fang
authors.initials: WF
authors.lastname: Zhang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000201:enzymology / Q000401:mortality / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011817:Rabbits; D011897:Random Allocation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D051742:Transcription Factor CHOP / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D000098:Acetophenones; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051742:Transcription Factor CHOP; C056165:acetovanillone; D019255:NADPH Oxidases
keywords: Endoplasmic reticulum stress; Left ventricular remodeling; Myocardial infarction; Myocyte apoptosis; NADPH oxidase