Eur J Pharmacol. 2012 Mar 5;678(1-3):32-8. doi: 10.1016/j.ejphar.2011.12.042. Epub 2012 Jan 12.
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.
