An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation
An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation
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DOI：
10.1073/pnas.0503723102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Stamler, JS
中科院分区：
文献类型：
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作者：
Chen, ZQ;Foster, MW;Stamler, JS
硝酸甘油（甘油三硝酸酯，GTN）通过其激发一氧化氮（NO）为基础的信号传导来扩张血管的细胞机制的身份仍然是心血管生物学中最长期的研究焦点和争议来源之一。最近的证据表明线粒体有一个意想不到的作用。我们在这里表明，生物转化的线粒体的临床相关浓度的GTN的结果在激活鸟苷酸环化酶，生产cGMP，血管舒张在体外，并降低血压在体内，这是消除的线粒体乙醛脱氢酶（mtALDH）的基因缺失。相反，替代性硝基（so）血管扩张剂产生的血管活性不受影响。在mtALDH（-/-）小鼠及其分离的血管组织中，GTN生物活性仍然可以产生，但仅在显著更高浓度的GTN下并且通过不表现出耐受性的机制产生。因此，mtALDH是必要的和足够的血管活性来源于治疗水平的GTN，更一般地说，线粒体可以作为一个来源的NO为基础的细胞信号，可能独立于NO合酶活性的起源。
The identity of the cellular mechanisms through which nitroglycerin (glyceryl trinitrate, GTN) elicits nitric oxide (NO)-based signaling to dilate blood vessels remains one of the longest standing foci of investigation and sources of controversy in cardiovascular biology. Recent evidence suggests an unexpected role for mitochondria. We show here that bioconversion by mitochondria of clinically relevant concentrations of GTN results in activation of guanylate cyclase, production of cGMP, vasodilation in vitro, and lowered blood pressure in vivo, which are eliminated by genetic deletion of the mitochondrial aldehyde dehydrogenase (mtALDH). In contrast, generation of vasoactivity from alternative nitro(so)vasodilators is unaffected. In mtALDH(-/-) mice and their isolated vascular tissue, GTN bioactivity can still be generated, but only at substantially higher concentrations of GTN and by a mechanism that does not exhibit tolerance. Thus, mtALDH is necessary and sufficient for vasoactivity derived from therapeutic levels of GTN, and, more generally, mitochondria can serve as a source of NO-based cellular signals that may originate independently of NO synthase activity.