Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.
Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.
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DOI：
10.1371/journal.pone.0008757
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发表时间：
2010-01-18
期刊：
影响因子：
3.7
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Guo R;Ren J
暴饮暴食和酒精中毒通常与心肌功能障碍有关，可能是由于乙醇代谢物乙醛的积累所致，尽管其潜在机制尚不清楚。本研究旨在利用心脏特异性乙醇脱氢酶 (ADH) 过度表达的小鼠模型来研究加速乙醇代谢对心肌收缩力、线粒体功能和细胞凋亡的影响。 ADH 和野生型 FVB 小鼠用乙醇（3 g/kg/d，腹腔注射）急性攻击 3 天。检查心肌收缩力、线粒体损伤和细胞凋亡（死亡受体和线粒体途径）。乙醇会导致心肌收缩力降低、心肌细胞增大、线粒体损伤和细胞凋亡，而 ADH 转基因则放大了这些影响。特别是，ADH 加剧了线粒体功能障碍，表现为线粒体膜电位降低和线粒体 O2 •− 积累。乙醇处理小鼠的心肌表现出 Bax、Caspase-3 表达增强和 Bcl-2 表达降低，其中除 Caspase-3 外，ADH 增强了其作用。 ADH 加剧了乙醇诱导的细胞质中线粒体死亡结构域成分 pro-caspase-9 和细胞色素 C 的增加。乙醇和 ADH 均不影响 ANP、总 caspase-9 前体、胞质和总 caspase-8 前体、TNF-α、Fas 受体、Fas L 和胞质 AIF 的表达。综上所述，这些数据表明，急性乙醇暴露后，ADH 过度表达导致乙醛产生增加，加剧了乙醇诱导的心肌收缩功能障碍、心肌细胞增大、线粒体损伤和细胞凋亡，表明 ADH 在乙醇诱导的心功能障碍中发挥着关键作用，可能是通过线粒体死亡途径 细胞凋亡。
Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O2 •−. Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-α, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.
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DOI：
10.1152/ajpheart.00780.2001
发表时间：
2002-04-01
影响因子：
4.8
作者：
Duan, JH;McFadden, GE;Ren, J
通讯作者：
Ren, J
影响因子：
24
作者：
Ma, Heng;Li, Ji;Ren, Jun
通讯作者：
Ren, Jun
DOI：
10.1073/pnas.96.14.8144
发表时间：
1999-07-06
影响因子：
11.1
作者：
Narula, J;Pandey, P;Kharbanda, S
通讯作者：
Kharbanda, S
影响因子：
56.9
作者：
LAPOSATA, EA;LANGE, LG
通讯作者：
LANGE, LG
影响因子：
3.2
作者：
Fadeel, B;Orrenius, S;Zhivotovsky, B
通讯作者：
Zhivotovsky, B