Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance
Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance
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DOI：
10.1172/jci200419267
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发表时间：
2004-02-01
影响因子：
15.9
通讯作者：
Münzel, T
中科院分区：
文献类型：
--
作者：
Sydow, K;Daiber, A;Münzel, T
最近的研究表明，线粒体乙醛脱氢酶(ALDH-2)在体内硝酸甘油(GTN)生物转化过程中起核心作用，其抑制作用是体外机制耐受的原因。ALDH-2在体内对GTN耐受性(对GTN的松弛功能受损)和交叉耐受(内皮依赖性松弛功能受损)的作用程度尚不清楚。用GTN治疗大鼠3天。输注伴随着血管ALDH-2活性、GTN生物转化和cGMP依赖激酶(CGK-I)活性的下降。此外，在对照血管中，多种ALDH-2抑制剂和底物可同时减少GTN对cGKI的刺激和GTN诱导的血管扩张，而这些药物对耐受性血管几乎没有影响。通过击倒线粒体DNA(罗氏度细胞)，在培养的内皮细胞中重现了一种功能耐受状态(在GTN/cGMP途径中)。此外，GTN增加了线粒体产生的活性氧(ROS)，这些增加与乙酰胆碱的松弛受损有关。最后，抗氧化剂/还原剂减少了线粒体ROS的产生，恢复了ALDH-2的活性。这些观察表明，硝酸盐耐受性至少在很大程度上是通过抑制血管ALDH-2介导的，线粒体ROS参与了这种抑制。因此，GTN耐受性可被视为以线粒体功能障碍为特征的代谢综合征。
Recent studies suggest that mitochondrial aldehyde dehydrogenase (ALDH-2) plays a central role in the process of nitroglycerin (glyceryl trinitrate, GTN) biotransformation in vivo and that its inhibition accounts for mechanism-based tolerance in vitro. The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross-tolerance (impaired endothelium-dependent relaxation) in vivo remain to be elucidated. Rats were treated for three days with GTN. Infusions were accompanied by decreases in vascular ALDH-2 activity, GTN biotransformation, and cGMP-dependent kinase (cGK-I) activity. Further, whereas in control vessels, multiple inhibitors and substrates of ALDH-2 reduced both GTN-stimulation of cGKI and GTN-induced vasodilation, these agents had little effect on tolerant vessels. A state of functional tolerance (in the GTN/cGMP pathway) was recapitulated in cultured endothelial cells by knocking down mitochondrial DNA (rhodegrees cells). In addition, GTN increased the production of reactive oxygen species (ROS) by mitochondria, and these increases were associated with impaired relaxation to acetylcholine. Finally, antioxidants/reductants decreased mitochondrial ROS production and restored ALDH-2 activity. These observations suggest that nitrate tolerance is mediated, at least in significant part, by inhibition of vascular ALDH-2 and that mitochondrial ROS contribute to this inhibition. Thus, GTN tolerance may be viewed as a metabolic syndrome characterized by mitochondrial dysfunction.