title: Alpha lipoic acid protects heart against myocardial ischemia-reperfusion injury through a mechanism involving aldehyde dehydrogenase 2 activation.
abstract: Recent studies demonstrate that alpha lipoic acid can prevent nitroglycerin tolerance by restoring aldehyde dehydrogenase 2 (ALDH2) activity and ALDH2-mediated detoxification of aldehydes is thought as an endogenous mechanism against ischemia-reperfusion injury. This study was performed to explore whether the cardioprotective effect of alpha lipoic acid was related to activation of ALDH2 and the underlying mechanisms. In a Langendorff model of ischemia-reperfusion in rats, cardiac function, activities of creatine kinase (CK) and ALDH2, contents of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) were measured. In a cell model of hypoxia-reoxygenation, the apoptosis, ALDH activity, reactive oxygen species level, 4-HNE and MDA contents were examined. In the isolated hearts, ischemia-reperfusion treatment led to cardiac dysfunction accompanied by an increase in 4-HNE and MDA contents. Pretreatment with lipoic acid significantly up-regulated myocardial ALDH2 activity concomitantly with an improvement of cardiac dysfunction and a decrease in 4-HNE and MDA contents, these effects were blocked by the inhibitor of ALDH2. Similarly, in the cultured cardiomyocytes, hypoxia-reoxygenation treatment induced apoptosis accompanied by an increase in the production of reactive oxygen species, 4-HNE and MDA. Administration of lipoic acid significantly up-regulated cellular ALDH2 activity concomitantly with a reduction in apoptosis, production of reactive oxygen species, 4-HNE and MDA, these effects were reversed in the presence of ALDH2 or PKCε inhibitors. Our results suggest that the cardioprotective effects of lipoic acid on ischemia-reperfusion injury are through a mechanism involving ALDH2 activation. The regulatory effect of lipoic acid on ALDH2 activity is dependent on PKCε signaling pathway.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Lan
authors.initials: L
authors.lastname: He
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Dai
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Zhang
authors.forename: Yi-Shuai
authors.initials: YS
authors.lastname: Zhang
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Luo
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000447:Aldehydes; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D008063:Thioctic Acid; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D003402:Creatine Kinase; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal