title: ALDH2 protects against stroke by clearing 4-HNE.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 Guo He Road, Shanghai 200433, China.
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Guo
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Liu
authors.forename: Pu
authors.initials: P
authors.lastname: Zang
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Dong
authors.forename: Li
authors.initials: L
authors.lastname: Ying
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Pu
authors.initials: P
authors.lastname: Xu
authors.forename: Xu-Rui
authors.initials: XR
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.forename: She-Qing
authors.initials: SQ
authors.lastname: Zhang
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Duan
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000097:blood* / Q000378:metabolism*; D000818:Animals; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000097:blood / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D024101:Mitochondrial Proteins; D008315:Malondialdehyde; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; C027576:4-hydroxy-2-nonenal