Yuan Fang, Lei Yonghong, Wang Qiurong, Esberg Lucy B, Huang Zaixing, Scott Glenda I, Li Xue, Ren Jun
Department of Orthopedics, Chinese PLA General Hospital, Beijing 100853, PR China.
Wound Healing and Cell Biology Laboratory, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100853, PR China.
Toxicol Lett. 2015 Mar 18;233(3):267-77. doi: 10.1016/j.toxlet.2014.12.018. Epub 2014 Dec 27.
Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca(2+) homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARγ coactivator 1α (PGC-1α)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca(2+) properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca(2+) rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca(2+) handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1α, SOD1 and interrupted intracellular Ca(2+) regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3β in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies as well as mitochondrial injury.
适量饮酒具有心脏保护作用，不过适度饮酒对肥胖人群心脏功能的作用仍不明确。本研究旨在探讨适度摄入乙醇对高脂饮食诱导的肥胖小鼠心肌功能的影响及其机制，重点关注线粒体完整性。在乙醇激发（1g/kg/d，持续3天）前，C57BL/6小鼠分别喂食低脂肪或高脂肪饮食16周。在最后一次乙醇激发后24小时，评估心脏收缩功能、细胞内Ca(2+)稳态、心肌组织学以及线粒体完整性[乌头酸酶活性和线粒体蛋白SOD1、UCP-2和PPARγ共激活因子1α（PGC-1α）]。高脂饮食会损害心肌细胞的收缩和细胞内Ca(2+)特性（降低峰值缩短和最大缩短/再延长速度，延长再延长持续时间，减弱细胞内Ca(2+)升高和清除，而不影响缩短持续时间）。虽然适度乙醇激发在低脂饮食摄入情况下未能改变心肌细胞的力学特性，但它加剧了高脂饮食摄入引起的心肌细胞收缩功能和细胞内Ca(2+)处理的变化。如苏木精-伊红染色所示，适度乙醇激发未能影响高脂饮食摄入引起的心脏肥大。高脂饮食摄入降低了心肌乌头酸酶活性，下调了线粒体蛋白UCP-2、PGC-1α、SOD1的水平，并中断了细胞内Ca(2+)调节蛋白，适度乙醇激发增强了这种作用。高脂饮食摄入和适度乙醇激发均未影响小鼠心脏中Akt和GSK3β的蛋白或mRNA水平以及磷酸化。综上所述，我们的数据表明，适度乙醇激发加剧了高脂饮食诱导的心脏收缩和细胞内Ca(2+)异常以及线粒体损伤。
