QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.084285v1 314/2/762    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Das, S. Articles by Das, D. K. Search for Related Content PubMed PubMed Citation Articles by Das, S. Articles by Das, D. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CARDIOVASCULAR

Resveratrol-Mediated Activation of cAMP Response Element-Binding Protein through Adenosine A₃ Receptor by Akt-Dependent and -Independent Pathways

Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut (S.D., N.M., D.K.D.); Department of Pharmacology, University of Debrecen, Debrecen, Hungary (S.D., A.T.); and Pharmacy Sciences, Creighton University Medical Center, Omaha, Nebraska (D.B.)

A recent study documented a role of adenosine A₃-Akt-cAMP response element-binding protein (CREB) survival signaling in resveratrol preconditioning of the heart. In this study, we demonstrate that resveratrol-mediated CREB activation can also occur through an Akt-independent pathway. Isolated rat hearts were perfused for 15 min with Krebs-Henseleit bicarbonate (KHB) buffer containing resveratrol in the absence or presence of adenosine A₃ receptor blocker MRS-1191 [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicar-boxylate], phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], mitogen-activated extracellular signal-regulated protein kinase inhibitor PD098059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], or a combination of LY294002 and PD098059. All hearts were subsequently subjected to 30-min ischemia followed by 2-h reperfusion. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis, and ventricular recovery. Resveratrol phosphorylated both Akt and CREB that was blocked by MRS-1191, which also abolished cardioprotective abilities of resveratrol. LY294002 completely inhibited Akt phosphorylation but partially blocked the phosphorylation of CREB. Inhibition of PI3-kinase also partially blocked resveratrol's ability to precondition the heart. PD098059 partially blocked the phosphorylation of CREB and resveratrol-mediated cardioprotection. Preperfusing the hearts with LY294002 and PD098059 together completely abolished the phosphorylation of CREB, simultaneously inhibiting resveratrol-mediated cardioprotection. The results indicate that resveratrol preconditions the hearts through adenosine A₃ receptor signaling that triggers the phosphorylation of CREB through both Akt-dependent and -independent pathways, leading to cardioprotection.

Address correspondence to: Dr. Dipak K. Das, Cardiovascular Research Center, University of Connecticut, School of Medicine, Farmington, CT 06030-1110. E-mail: ddas{at}neuron.uchc.edu

This article has been cited by other articles:

				K. Venkatachalam, S. Mummidi, D. M. Cortez, S. D. Prabhu, A. J. Valente, and B. Chandrasekar Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2078 - H2087. [Abstract] [Full Text] [PDF]

				L. H. Opie and S. Lecour The red wine hypothesis: from concepts to protective signalling molecules Eur. Heart J., July 2, 2007; 28(14): 1683 - 1693. [Abstract] [Full Text] [PDF]

				N. Nagy, G. Malik, A. B. Fisher, and D. K. Das Targeted disruption of peroxiredoxin 6 gene renders the heart vulnerable to ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2636 - H2640. [Abstract] [Full Text] [PDF]

				I. Bak, I. Lekli, B. Juhasz, N. Nagy, E. Varga, J. Varadi, R. Gesztelyi, G. Szabo, L. Szendrei, I. Bacskay, et al. Cardioprotective mechanisms of Prunus cerasus (sour cherry) seed extract against ischemia-reperfusion-induced damage in isolated rat hearts Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1329 - H1336. [Abstract] [Full Text] [PDF]

				S. Das, A. Tosaki, D. Bagchi, N. Maulik, and D. K. Das Potentiation of a Survival Signal in the Ischemic Heart by Resveratrol through p38 Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1/cAMP Response Element-Binding Protein Signaling J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 980 - 988. [Abstract] [Full Text] [PDF]

				D. K. Das and N. Maulik Cardiac genomic response following preconditioning stimulus Cardiovasc Res, May 1, 2006; 70(2): 254 - 263. [Abstract] [Full Text] [PDF]