ALDH2 protects against stroke by clearing 4-HNE.
ALDH2 protects against stroke by clearing 4-HNE.
复制标题
ALDH2 通过清除 4-HNE 预防中风
作者：
醛脱氢酶2（ALDH 2）是代谢乙醇和有毒醛如4-羟基-2-壬烯醛（4-HNE）的线粒体酶。使用公正的蛋白质组学搜索，我们确定了ALDH 2缺乏中风倾向的自发性高血压大鼠（SHR-SP）相比，自发性高血压大鼠（SHR）。我们得出结论，ALDH 2缺乏在神经元损伤中的致病作用，因为在体外研究中ALDH 2的过表达或激活通过清除4-HNE赋予神经保护作用。此外，ALDH 2敲低大鼠显示PKCε的神经保护作用的缺乏。已知适度的乙醇给药可预防卒中，可增强4-HNE的解毒作用，并通过PKCε-ALDH 2途径预防缺血性脑损伤。SHR-SP组血清4-HNE水平持续升高，并与寿命呈负相关。中风后至少6个月内其血浆水平持续升高也表明4-HNE在人类中风中的作用。最后，我们观察到1242例随访8年的卒中患者中有21例的初始血浆4-HNE水平高于未发生卒中的患者。这些发现表明，ALDH 2通路的激活可能作为一个有用的指标，在识别中风倾向的主题，和ALDH 2通路可能是一个潜在的目标，治疗干预中风。
Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE). Using an unbiased proteomic search, we identified ALDH2 deficiency in stroke-prone spontaneously hypertensive rats (SHR-SP) as compared with spontaneously hypertensive rats (SHR). We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4-HNE in in vitro studies. Further, ALDH2-knockdown rats revealed the absence of neuroprotective effects of PKCε. Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4-HNE, and to protect against ischemic cerebral injury through the PKCε-ALDH2 pathway. In SHR-SP, serum 4-HNE level was persistently elevated and correlated inversely with the lifespan. The role of 4-HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke. Lastly, we observed that 21 of 1 242 subjects followed for 8 years who developed stroke had higher initial plasma 4-HNE levels than those who did not develop stroke. These findings suggest that activation of the ALDH2 pathway may serve as a useful index in the identification of stroke-prone subjects, and the ALDH2 pathway may be a potential target of therapeutic intervention in stroke.
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影响因子：
37.3
作者：
Gorin MA;Pan Q
通讯作者：
Pan Q
影响因子：
9.3
作者：
Budas, Grant R.;Disatnik, Marie-Helene;Mochly-Rosen, Dana
通讯作者：
Mochly-Rosen, Dana
影响因子：
56.9
作者：
Lee, SH;Oe, T;Blair, IA
通讯作者：
Blair, IA
影响因子：
37.8
作者：
Jauch, Edward C.;Cucchiara, Brett;Hazinski, Mary Fran
通讯作者：
Hazinski, Mary Fran
DOI：
10.1073/pnas.95.2.510
发表时间：
1998-01-20
影响因子：
11.1
作者：
Lucas, DT;Szweda, LI
通讯作者：
Szweda, LI