Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits

• Published in: Biochimica et biophysica acta 2015-05, Vol.1852 (5), p.805-815
• Main Authors: Li, Bao, Tian, Jing, Sun, Yi, Xu, Tao-Rui, Chi, Rui-Fang, Zhang, Xiao-Li, Hu, Xin-Ling, Zhang, Yue-an, Qin, Fu-Zhong, Zhang, Wei-Fang
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Angiotensin II - pharmacology; Animals; Apoptosis - drug effects; Blotting, Western; Cell Line; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Heat-Shock Proteins - metabolism; Left ventricular remodeling; Microscopy, Confocal; Myocardial infarction; Myocardial Infarction - enzymology; Myocardial Infarction - mortality; Myocardial Infarction - physiopathology; Myocyte apoptosis; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; NADPH oxidase; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Rabbits; Random Allocation; Rats; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Survival Rate; Transcription Factor CHOP - metabolism; Vasoconstrictor Agents - pharmacology; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.01.010

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 30days. The agents were administered beginning at 1week 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. •NADPH oxidase Nox2 was increased in myocytes in the remote non-infarcted myocardium.•NADPH oxidase activation coincided with increased GRP78 and CHOP protein expressions.•NADPH oxidase inhibition attenuates endoplasmic reticulum (ER) stress and apoptosis.•NADPH oxidase activation mediates ER stress and post-infarction cardiac remodeling.