Chronic alcohol intake-induced oxidative stress and apoptosis: role of CYP2E1 and calpain-1 in alcoholic cardiomyopathy
Chronic alcohol intake-induced oxidative stress and apoptosis: role of CYP2E1 and calpain-1 in alcoholic cardiomyopathy
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DOI：
10.1007/s11010-011-1022-z
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发表时间：
2012-01-01
影响因子：
4.3
通讯作者：
Zhou, Li-jun
中科院分区：
文献类型：
--
作者：
Jing, Ling;Jin, Cheng-mei;Zhou, Li-jun
在许多实验模型中，细胞色素P-450 2 E1 CYP 2 E1诱导与氧化应激有关。本研究旨在探讨酒精性心肌病（ACM）发生发展过程中CYP 2 E1活性与氧化应激和心肌细胞凋亡的关系。治疗6个月后，在4组慢性仪器狗（对照;酒精接收;和酒精接收加缬沙坦或卡尼汀治疗）中评价左心室形态学的变化。Western blotting法检测CYP 2 E1和calpain-1蛋白表达，TUNEL法和免疫组化法检测细胞凋亡。丙二醛水平作为氧化应激的标志物进行评估，而超氧化物歧化酶和谷胱甘肽过氧化物酶水平作为抗氧化防御机制的标志物进行评估。饮酒组CYP 2 E1的表达较对照组增加（P < 0.05），且与氧化应激有关。同样，Bad和calpain-1蛋白的表达在慢性酒精暴露后增加，而Bcl-x（L）蛋白的表达保持在低水平。缬沙坦和卡尼汀均能显著抑制Bad和calpain-1蛋白的表达，而增加Bcl-x（L）蛋白的表达（P < 0.05）。总的来说，我们的研究结果表明，CYP 2 E1在与慢性酒精中毒相关的氧化应激中可能发挥重要作用。氧化应激的增加伴随着细胞凋亡，并可能最终导致组织重塑和ACM。重要的是，这些酒精诱导的作用可以通过血管紧张素1受体阻断剂或肉毒碱补充剂等手段消除。
Cytochrome P-450 2E1 CYP2E1 induction has been linked to oxidative stress in a number of experimental models. The aim of this study was to investigate the relationship between CYP2E1 activity and markers of oxidative stress and cardiac cell apoptosis during the development of alcoholic cardiomyopathy (ACM). Changes in left ventricular morphology were evaluated in 4 groups of chronically instrumented dogs (control; alcohol-receiving; and alcohol-receiving plus treatment with either valsartan or carnitine) after 6 months of treatment. CYP2E1 and calpain-1 protein expression were determined by Western blotting, and apoptosis evaluated by TUNEL and immunohistochemistry. Malonyl dialdehyde levels were assessed as a marker of oxidative stress, while superoxide dismutase and glutathione peroxidase levels were evaluated as markers of antioxidant defense mechanisms. Expression of CYP2E1 was increased in the alcohol-receiving group compared with controls (P < 0.05) and was associated with oxidative stress. Similarly, expression of Bad and calpain-1 protein was increased after chronic alcohol exposure, while Bcl-x(L) protein expression remained at a low level. Bad and calpain-1 protein expressions were significantly inhibited by treatment with valsartan or carnitine, while expression of Bcl-x(L) protein was increased (P < 0.05). Collectively, our results indicate a possibly significant role for CYP2E1 in the oxidative stress associated with chronic alcoholism. The resulting increase in oxidative stress is accompanied by cellular apoptosis and may ultimately contribute to tissue remodeling and ACM. Importantly, these alcohol-induced effects may be abrogated by means such as angiotensin 1 receptor blockade or carnitine supplementation.