Chinese-American Research Institute for Diabetic Complications & School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan University-Town, Wenzhou, Zhejiang, China.
Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Toxicol Sci. 2017 Oct 1;159(2):392-401. doi: 10.1093/toxsci/kfx140.
Heavy consumption of alcohol induces cardiomyopathy and is associated with metabolic changes in the heart. The role of altered metabolism in the development of alcoholic cardiomyopathy remains largely unknown but is examined in the present study. The effect of chronic alcohol consumption on cardiac damage was examined in mice fed an alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced metabolic alteration and pathologic changes were examined in both animal hearts and H9c2 cell cultures. Compared with controls, the hearts from the alcohol-fed mice exhibited cardiac oxidative stress, cell death, a fibrotic response, hypertrophic remodeling, and the eventual development of cardiac dysfunction. All these detrimental effects could be ameliorated by superoxide dismutase mimic Mn (111) tetrakis 1-methyl 4-pyridylporphyrin pentachloride (MnTMPyP) therapy. A mechanistic study showed that chronic alcohol exposure enhanced the expression of proteins regulating fatty acid uptake but impaired the expression of proteins involved in mitochondrial fatty acid oxidation, which compensatively geared the heart to the suboptimal energy source, glucose. However, chronic alcohol exposure also impaired the glycolytic energy production step regulated by glyceraldehyde-3-phosphate dehydrogenase, which further feeds back to enhance glucose uptake signaling and the accumulation of glycolytic intermediate product fructose, resulting in aggravation of alcohol-induced cardiac oxidative stress, cell death, and remodeling. All these dysmetabolic alterations could be normalized by MnTMPyP treatment, along with significant improvement in cardiac cell death and remodeling. These results demonstrate that alcohol-induced oxidative stress and altered glucose metabolism are causal factors for the development of alcoholic cardiomyopathy.
大量饮酒可诱发心肌病,并与心脏代谢变化有关。改变的代谢在酒精性心肌病的发展中的作用在很大程度上尚不清楚,但本研究对此进行了探讨。本研究在给予酒精或等热量对照饮食 2 个月的小鼠中,研究了慢性酒精消耗对心脏损伤的影响。在动物心脏和 H9c2 细胞培养物中检查了酒精诱导的代谢改变和病理变化的信号通路。与对照组相比,酒精喂养的小鼠心脏表现出心脏氧化应激、细胞死亡、纤维化反应、肥大重塑以及最终发生的心脏功能障碍。超氧化物歧化酶模拟物 Mn(111)四聚体 1-甲基-4-吡啶基卟啉五氯化物(MnTMPyP)治疗可改善所有这些有害影响。一项机制研究表明,慢性酒精暴露增强了调节脂肪酸摄取的蛋白质的表达,但损害了参与线粒体脂肪酸氧化的蛋白质的表达,这使心脏代偿性地适应了次优的能量来源葡萄糖。然而,慢性酒精暴露也损害了由甘油醛-3-磷酸脱氢酶调节的糖酵解能量产生步骤,这进一步反馈增强葡萄糖摄取信号和糖酵解中间产物果糖的积累,导致酒精诱导的心脏氧化应激、细胞死亡和重塑加重。MnTMPyP 治疗可使所有这些代谢紊乱得到纠正,并显著改善心脏细胞死亡和重塑。这些结果表明,酒精诱导的氧化应激和葡萄糖代谢改变是酒精性心肌病发展的因果因素。