title: Prevalent role of Akt and ERK activation in cardioprotective effect of Ca(2+) channel- and beta-adrenergic receptor blockers.
abstract: We studied cardioprotective as well as Akt and extracellular signal-activated kinase (ERK) activating effect of a Ca(2+) antagonist and a beta-adrenergic receptor blocker during ischemia-reperfusion, and compared these properties of the substances with that of a poly(ADP-ribose) polymerase (PARP) inhibitor used as a positive control throughout the experiments. Langendorff-perfused isolated rat hearts were subjected to 25 min global ischemia followed by 45 min reperfusion, and recovery of energy metabolism as well as functional cardiac parameters were monitored. Although to varying extents, all substances improved recovery of creatine phosphate, ATP, intracellular pH, and reutilization of inorganic phosphate. These favorable changes were accompanied by improved recovery of heart function parameters and reduced infarct size. In addition and again to varying extents, all studied substances decreased oxidative damage (lipid peroxidation and protein oxidation), and activated Akt, glycogen synthase kinase (GSK)-3beta, and ERK1/2. Correlation between cardioprotective and kinase activating effectivity of the compounds proved to be statistically significant. Physiological significance of these kinase activations was established by demonstrating that inhibition of Akt by LY294002 and ERK1/2 by PD98059 compromised the cardioprotective effect of all the substances studied. In conclusion, we demonstrated for the first time that activation of phosphatidylinositol-3-kinase (PI-3K)-Akt and ERK2 pathways significantly contributed to cardioprotective effects of a Ca(2+) antagonist and a beta-adrenergic receptor blocker. Furthermore, we found a strong correlation between cardioprotective and kinase-activating potencies of the substances studied (Verapamil, Metoprolol and two PARP inhibitors), which indicated the potentiality of these kinases as drug-targets in the therapy of ischemic heart disease.
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, Pecs, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
authors.forename: Katalin
authors.initials: K
authors.lastname: Hanto
authors.forename: Zita
authors.initials: Z
authors.lastname: Bognar
authors.forename: Antal
authors.initials: A
authors.lastname: Tapodi
authors.forename: Eszter
authors.initials: E
authors.lastname: Bognar
authors.forename: Gyongyi N
authors.initials: GN
authors.lastname: Kiss
authors.forename: Aliz
authors.initials: A
authors.lastname: Szabo
authors.forename: Gabor
authors.initials: G
authors.lastname: Rappai
authors.forename: Tamas
authors.initials: T
authors.lastname: Kiss
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015227:Lipid Peroxidation; D008297:Male; D008790:Metoprolol / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010710:Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014700:Verapamil / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; C508983:HO 3089; D010710:Phosphates; D017382:Reactive Oxygen Species; D014700:Verapamil; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D008790:Metoprolol