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
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 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.
Biochim Biophys Acta. 2015 May;1852(5):805-15. doi: 10.1016/j.bbadis.2015.01.010. Epub 2015 Jan 21.
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.
心肌梗死后，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性和内质网（ER）应激增加。在本研究中，我们旨在测试梗死心肌远处的非梗死心肌中NADPH氧化酶的激活是否介导心肌梗死后的ER应激和左心室（LV）重塑。将心肌梗死或假手术的兔子随机分为口服NADPH氧化酶抑制剂阿朴吗啡或安慰剂30天。药物在手术后1周开始给药。心肌梗死兔子的左心室缩短分数、左心室射血分数和左心室压力上升的一阶导数降低，阿朴吗啡治疗可消除这些降低。心肌梗死后，梗死心肌远处的非梗死心肌中NADPH氧化酶Nox2蛋白和mRNA表达增加。免疫标记进一步显示，远处心肌的心肌细胞中Nox2增加。阿朴吗啡治疗可防止远处心肌中Nox2表达、NADPH氧化酶活性、氧化应激、心肌细胞凋亡以及GRP78、CHOP和半胱天冬酶12裂解蛋白表达的增加。阿朴吗啡治疗还减轻了心肌细胞直径增加和心肌纤维化。在暴露于血管紧张素II（心肌梗死后重塑的重要刺激物）的培养H9C2心肌细胞中，用小干扰RNA敲低Nox2可显著抑制血管紧张素II诱导的NADPH氧化酶激活、活性氧以及GRP78和CHOP蛋白表达。我们得出结论，抑制NADPH氧化酶可减轻梗死心肌远处的非梗死心肌中ER应激增加以及兔子心肌梗死后晚期的左心室重塑。这些发现表明，梗死心肌远处的非梗死心肌中NADPH氧化酶的激活介导ER应激增加，导致心肌梗死后的心肌细胞凋亡和左心室重塑。
