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Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A₃ receptor activation

Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut

Submitted 25 May 2004 ; accepted in final form 28 July 2004

Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 µM resveratrol; 3) 10 µM resveratrol + 1 µM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A₁ receptor blocker); 4) 10 µM resveratrol + 1 µM 8-(3-chlorostyryl)caffeine (CSC; adenosine A_2a receptor blocker); 5) 10 µM resveratrol + 1 µM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A₃ receptor blocker); or 6) 10 µM resveratrol + 3 µM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A₁ and A₃ receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A₁ and A₃ receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.

Akt; cAMP response element-binding protein; Bad; apoptosis

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