Impact of a novel cardioprotective agent on the ischaemia-reperfusion-induced Akt kinase activation.
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.
Toth
Ambrus
A
First Department of Medicine, Division of Cardiology, University of Pecs Medical School, H-7624, Pecs, Ifjusag u. 13, Hungary.
Kovacs
Krisztina
K
Deres
Peter
P
Halmosi
Robert
R
Czopf
Laszlo
L
Hanto
Katalin
K
Kalai
Tamas
T
Hideg
Kalman
K
Sumegi
Balazs
B
Toth
Kalman
K
D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects
D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; C480018:HO3073; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt