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

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 10 microM) and/or wortmannin (100 nM, 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-3 beta (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.

• Authors: Ambrus Toth, Krisztina Kovacs, Peter Deres, Robert Halmosi, Laszlo Czopf, Katalin Hanto, Tamas Kalai, Kalman Hideg, Balazs Sumegi, Kalman Toth
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 66 Issue 11 Pg. 2263-72 (Dec 01 2003) ISSN: 0006-2952 [Print] England
• PMID: 14609750 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Free Radical Scavengers
• HO3073
• Proto-Oncogene Proteins
• Pyridines
• Akt1 protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cardiotonic Agents (chemistry, pharmacology, therapeutic use)
• Enzyme Activation (drug effects, physiology)
• Free Radical Scavengers (chemistry, pharmacology, therapeutic use)
• Male
• Myocardial Ischemia (drug therapy, enzymology)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Pyridines (chemistry, pharmacology)
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, enzymology)
• Signal Transduction (drug effects)