Akt activation induced by an antioxidant compound during ischemia-reperfusion

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Abstract

Molecular mechanisms of cardioprotection afforded by modified mexiletine compounds were investigated during ischemia-reperfusion (IR) in Langendorff perfused hearts. Rat hearts were subjected to a global 25 min ischemia followed by reperfusion, either untreated or treated with mexiletine, or three substituted mexiletine derivates (5 μM). A modified mexiletine derivative (H-2693) promoted best the recovery of myocardial energy metabolism (assessed by 31P NMR spectroscopy) compared to untreated and mexiletine-treated hearts. H-2693 also preserved cardiac contractile function and attenuated the IR-induced lipid peroxidation (TBARS formation) and protein oxidation (carbonyl content). Western blot revealed that H-2693 propagated the phosphorylation of Akt (activation) and its downstream substrate glycogen synthase kinase-3β (GSK-3β, inactivation) compared to untreated IR. Parallel treatment with the phosphatidylinositol-3-kinase (upstream activator of Akt) inhibitor wortmannin (100 nM) abolished the beneficial effects of H-2693 on energetics and function, and reduced Akt and GSK-3β phosphorylation. As a result of the antiapoptotic impacts of Akt activation, H-2693 decreased caspase-3 activity, which was neutralized by wortmannin. Here we first demonstrated that a free radical-entrapping compound could activate the prosurvival Akt pathway beyond its proven ability to scavenge reactive oxygen species. In conclusion, the favorable influence of H-2693 on signaling events during IR may have considerably contributed to its cardioprotective effect.

Original languageEnglish
Pages (from-to)1051-1063
Number of pages13
JournalFree Radical Biology and Medicine
Volume35
Issue number9
DOIs
Publication statusPublished - Nov 1 2003

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Keywords

  • Free radicals
  • Ischemia-reperfusion
  • Scavenger
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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