Prevalent role of Akt and ERK activation in cardioprotective effect of Ca2+ channel- and beta-adrenergic receptor blockers

Krisztina Kovacs, Katalin Hanto, Z. Bognár, Antal Tapodi, Eszter Bognar, Gyongyi N. Kiss, A. Szabó, Gabor Rappai, Tamas Kiss, B. Sümegi, F. Gallyas

Research output: Contribution to journalArticle

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Abstract

We studied cardioprotective as well as Akt and extracellular signal-activated kinase (ERK) activating effect of a Ca2+ 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)-3β, 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 Ca2+ antagonist and a β-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.

Original languageEnglish
Pages (from-to)155-164
Number of pages10
JournalMolecular and Cellular Biochemistry
Volume321
Issue number1-2
DOIs
Publication statusPublished - 2009

Fingerprint

Adrenergic beta-Antagonists
Receptors, Adrenergic, beta
Phosphotransferases
Chemical activation
Recovery
Reperfusion
Ischemia
Phosphatidylinositol 3-Kinase
Glycogen Synthase Kinase 3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Metoprolol
Adrenergic Antagonists
Phosphocreatine
Recovery of Function
Verapamil
Adrenergic Receptors
Energy Metabolism
Lipid Peroxidation
Myocardial Ischemia
Rats

Keywords

  • Akt
  • Beta-adrenergic receptor blocker
  • Ca-channel blocker
  • ERK
  • Ischemia-reperfusion

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Prevalent role of Akt and ERK activation in cardioprotective effect of Ca2+ channel- and beta-adrenergic receptor blockers. / Kovacs, Krisztina; Hanto, Katalin; Bognár, Z.; Tapodi, Antal; Bognar, Eszter; Kiss, Gyongyi N.; Szabó, A.; Rappai, Gabor; Kiss, Tamas; Sümegi, B.; Gallyas, F.

In: Molecular and Cellular Biochemistry, Vol. 321, No. 1-2, 2009, p. 155-164.

Research output: Contribution to journalArticle

Kovacs, Krisztina ; Hanto, Katalin ; Bognár, Z. ; Tapodi, Antal ; Bognar, Eszter ; Kiss, Gyongyi N. ; Szabó, A. ; Rappai, Gabor ; Kiss, Tamas ; Sümegi, B. ; Gallyas, F. / Prevalent role of Akt and ERK activation in cardioprotective effect of Ca2+ channel- and beta-adrenergic receptor blockers. In: Molecular and Cellular Biochemistry. 2009 ; Vol. 321, No. 1-2. pp. 155-164.
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AU - Tapodi, Antal

AU - Bognar, Eszter

AU - Kiss, Gyongyi N.

AU - Szabó, A.

AU - Rappai, Gabor

AU - Kiss, Tamas

AU - Sümegi, B.

AU - Gallyas, F.

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