NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.
NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.
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DOI：
10.1038/srep32554
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发表时间：
2016-09-14
影响因子：
4.6
通讯作者：
Wenzel P
中科院分区：
文献类型：
--
作者：
Brandt M;Garlapati V;Oelze M;Sotiriou E;Knorr M;Kröller-Schön S;Kossmann S;Schönfelder T;Morawietz H;Schulz E;Schultheiss HP;Daiber A;Münzel T;Wenzel P
酒精性心肌病（ACM）是由过量饮酒引起的心力衰竭（HF）的重要原因。虽然人们认为乙醇（EtOH）代谢产物乙醛（ACA）的心脏毒性是其发展和进展的核心，但确切的机制仍不清楚。暴露于ACA或EtOH的小鼠心肌细胞（CM）显示超氧化物（O2·−）水平升高和线粒体极化降低，两者均通过NADPH氧化酶（NOX）抑制而正常化。C57 BL/6小鼠和缺乏ACA降解酶线粒体醛脱氢酶（ALDH-2−/−）的小鼠被喂食2%乙醇饮食5周，造成ACA过载。与喂食2%EtOH的C57 BL/6小鼠相比，喂食2%EtOH的ALDH-2−/−小鼠表现出心脏功能下降，心脏与身体和肺与身体的重量比增加，脂质过氧化产物丙二醛（MDA）的心脏水平增加，以及NOX活性和NOX 2/糖蛋白91 phox（NOX 2/gp 91 phox）亚基表达增加。超声心动图显示，ALDH-2−/−/gp 91 phox −/−小鼠在5周的2%EtOH饮食后免受ACA过载诱导的HF的影响，这表明NOX 2衍生的O2·−有助于ACM的发展。翻译到人类病理生理学，我们发现增加gp 91 phox表达在内膜活检ACM患者。总之，ACM是由ACA驱动的线粒体功能障碍促进的，并且可以通过消融NOX 2/gp 91 phox来改善。因此，NOX 2/gp 91 phox可能是治疗ACM的潜在药理学靶点。
Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2•−) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2−/−) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2−/− mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91phox (NOX2/gp91phox) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2−/−/gp91phox−/− mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2•− contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91phox expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91phox. NOX2/gp91phox therefore might be a potential pharmacological target to treat ACM.
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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：
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影响因子：
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影响因子：
3.7
作者：
Guo R;Ren J
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影响因子：
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作者：
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