ALDH2 protects against stroke by clearing 4-HNE

作者：Guo, Jin-Min; Liu, Ai-Jun; Zang, Pu; Dong, Wen-Zhe; Ying, Li; Wang, Wei; Xu, Pu; Song, Xu-Rui; Cai, Jun; Zhang, She-Qing; Duan, Jun-Li; Mehta, Jawahar L.; Su, Ding-Feng^*

来源：Cell Research, 2013, 23(7): 915-930.

DOI：10.1038/cr.2013.69

• ALDH2
• 4-HNE
• stroke
• ethanol

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 PKCe. 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 PKCe-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.

• 出版日期2013-7
• 单位首都医科大学; 中国人民解放军第二军医大学; 上海交通大学; 中国人民解放军济南军区总医院