Impact of a novel cardioprotective agent on the ischaemia-reperfusion- induced Akt kinase activation

Ambrus Toth, Krisztina Kovacs, Peter Deres, Robert Halmosi, Laszlo Czopf, Katalin Hanto, Tamas Kalai, Kalman Hideg, Balazs Sumegi, Kalman Toth

Research output: Article

17 Citations (Scopus)

Abstract

Cardioprotective effect of a free radical-scavenging compound (HO-3073) was examined during ischaemia-reperfusion (IR) in isolated heart perfusion system and its influence on the pro-survival Akt signalling pathway was addressed. Rat hearts were perfused according to the Langendorff method and subjected to a global 25-min ischaemia and 15, 45 and 90-min reperfusion either untreated or treated with HO-3073 (2, 5 and 10μM) and/or wortmannin (100nM, inhibitor of phosphatidylinositol-3-kinase). HO-3073 facilitated the recovery of myocardial energy metabolism as assessed by 31P NMR spectroscopy (creatine phosphate recovery in reperfusion was 76±5%, while in untreated hearts 32±4%). Functional performance of the hearts followed by a left ventricular balloon manometer was also markedly improved by HO-3073 administration (recovery of rate-pressure product related to normoxia was 47±3%, while in untreated hearts 12±3%). HO-3073 diminished the infarct size measured by TTC staining (29±6% as opposed to 64±7% in untreated ischaemia-reperfusion). HO-3073 also significantly attenuated lipid peroxidation (thiobarbituric acid reactive substances) and protein oxidation (protein carbonyl content) compared to untreated hearts. HO-3073 enhanced the ischaemia-reperfusion-triggered phosphorylation of Akt-1 (activation) and glycogen synthase kinase-3β (inactivation) as evidenced by Western blot analysis. Wortmannin co-administration neutralised the beneficial effects of HO-3073 on cardiac energetics, contractile function, infarct size, as well as Akt signalling. Our results first display that a radical-scavenging molecule possesses the ability to intensify the pro-survival functioning of phosphatidylinositol-3-kinase/Akt pathway, which is presumed to play an additive role in the cardioprotective properties of HO-3073.

Original languageEnglish
Pages (from-to)2263-2272
Number of pages10
JournalBiochemical Pharmacology
Volume66
Issue number11
DOIs
Publication statusPublished - dec. 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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