Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis
Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis
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DOI：
10.1152/ajpheart.00214.2016
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发表时间：
2016-06-01
影响因子：
4.8
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Matyas, Csaba;Varga, Zoltan V.;Pacher, Pal
人类酒精性心肌病的发展是对慢性过量饮酒的反应；然而，缺乏良好的小鼠酒精性心肌病模型。在此，我们描述了慢性和暴饮乙醇（EtOH）喂养引起的酒精性心肌病小鼠模型，并描述了这些模型中详细的血流动力学改变、线粒体功能和氧化还原信号。小鼠分别饲喂含5%乙酸乙酯的液体饲料10、20和40天(d)，并分别饲喂单次或多次乙酸乙酯（5 g/kg体重）。等热量配对喂养的小鼠作为对照。采用有创压力-容积传导法和超声心动图评价左心室功能和形态。检测线粒体复合体（I、II、IV）活性、3-硝基酪氨酸（3-NT）水平、氧化应激标志物（gp91phox、p47phox）、线粒体生物发生（PGC1 α、过氧化物酶体增殖物激活受体α）和纤维化的基因表达。采用组织学/免疫组化方法研究心脏脂肪变性和纤维化。慢性和暴食EtOH组（EtOH加单次暴食组已在10天）表现为收缩功能障碍（收缩期末期压力-容积关系斜率和负荷前可再生卒中功降低）、舒张功能障碍（左室压衰减时间常数和收缩压衰减最大斜率降低）和血管功能障碍（动脉弹性受损和总外周阻力降低）。同时伴有心肌氧化/硝化应激（3-NT、gp91phox、p47phox、血管紧张素II受体，1a型）增强，线粒体复合体I、II、IV活性和线粒体生物发生恶化，心脏过度脂肪变性和死亡率升高。总的来说，小鼠慢性暴饮暴食EtOH会导致酒精诱导的心肌病（国家酒精滥用和酒精中毒研究所模型），其特征是心肌氧化/硝化应激增加，线粒体功能和生物发生受损，心脏脂肪变性加剧。
Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1 alpha, peroxisome proliferator-activated receptor alpha), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis.