Wenzel Philip, Müller Johanna, Zurmeyer Sarah, Schuhmacher Swenja, Schulz Eberhard, Oelze Matthias, Pautz Andrea, Kawamoto Toshihiro, Wojnowski Leszek, Kleinert Hartmut, Münzel Thomas, Daiber Andreas
II. Medizinische Klinik, Labor für Molekulare Kardiologie, Johannes-Gutenberg-Universität Mainz, Langenbeck Str. 1, 55131 Mainz, Germany.
Biochem Biophys Res Commun. 2008 Feb 29;367(1):137-43. doi: 10.1016/j.bbrc.2007.12.089. Epub 2007 Dec 26.
Mitochondrial aldehyde dehydrogenase (ALDH-2) reduces reactive oxygen species (ROS) formation related to toxic aldehydes; additionally, it provides a bioactivating pathway for nitroglycerin. Since acetaldehyde, nitroglycerin, and doxorubicin treatment provoke mitochondrial oxidative stress, we used ALDH-2(-/-) mice and purified recombinant human ALDH-2 to test the hypothesis that ALDH-2 has an indirect antioxidant function in mitochondria. Antioxidant capacity of purified ALDH-2 was comparable to equimolar doses of glutathione, cysteine, and dithiothreitol; mitochondrial oxidative stress was comparable in C57Bl6 and ALDH-2(-/-) mice after acute challenges with nitroglycerin or doxorubicin, whereas chronic acetaldehyde, nitroglycerin, and doxorubicin treatment dose-dependently increased mitochondrial ROS formation and impaired endothelial function to a greater extent in ALDH-2(-/-) mice. Maximal nitroglycerin dose applied in vivo lead to a "super-desensitized" nitroglycerin response in isolated ALDH-2(-/-) aortas, inaccessible in C57Bl6 mice. Our results suggest that ALDH-2 has an indirect antioxidative property independent of its thiol-moiety in disease states of cardiovascular oxidative stress.
线粒体醛脱氢酶（ALDH-2）可减少与有毒醛类相关的活性氧（ROS）生成；此外，它还为硝酸甘油提供了一条生物活化途径。由于乙醛、硝酸甘油和阿霉素处理会引发线粒体氧化应激，我们使用ALDH-2基因敲除小鼠和纯化的重组人ALDH-2来验证ALDH-2在线粒体中具有间接抗氧化功能这一假说。纯化的ALDH-2的抗氧化能力与等摩尔剂量的谷胱甘肽、半胱氨酸和二硫苏糖醇相当；在使用硝酸甘油或阿霉素进行急性刺激后，C57Bl6小鼠和ALDH-2基因敲除小鼠的线粒体氧化应激相当，而长期给予乙醛、硝酸甘油和阿霉素处理会使ALDH-2基因敲除小鼠的线粒体ROS生成呈剂量依赖性增加，并在更大程度上损害内皮功能。体内应用的最大硝酸甘油剂量在分离的ALDH-2基因敲除小鼠主动脉中导致了一种C57Bl6小鼠无法出现的“超脱敏”硝酸甘油反应。我们的结果表明，在心血管氧化应激疾病状态下，ALDH-2具有一种独立于其硫醇部分的间接抗氧化特性。
