Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB.
Recent studies have demonstrated that resveratrol (trans-3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, can pharmacologically precondition (PC) the heart through a nitric oxide (NO)-dependent and adenosine receptors-mediated mechanism. Since NO can induce the expression of heme oxygenase-1 (HO-1), we examined if HO-1 induction has a direct role in resveratrol-preconditioning of the heart. Eight groups of rats were studied during 7 days: (i) control rats; (ii) rats receiving resveratrol (gavage, 2.5 mg/kg); (iii) rats injected tin protoporphyrin (SnPP), a HO-1 inhibitor, i.p. on days 1, 3 and 6; (iv) rats injected 202190 (SB), a p38MAPK inhibitor, i.p. for 7 days; (v) rats injected 294002 (LY), a Akt inhibitor, i.p. for 7days; (vi) rats receiving resveratrol and SnPP; (vii) rats receiving resveratrol and SB; and (viii) rats receiving resveratrol and LY. After the treatments, the rats were sacrificed, and the hearts isolated and subjected to 30 min global ischemia followed by 2 h of reperfusion. The results shown a significant cardioprotection with resveratrol as evidenced by superior post-ischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes. SnPP treatment abolished the cardioprotective effect of resveratrol. Resveratrol induced the activation of nuclear factor kappa-beta(NFkappaB), the phosphorylation of p38MAP kinase beta and Akt, as well as the inhibition of p38 MAP kinase alpha; all these effects but the activation of NFkappaB, were completely reversed by treatment with SnPP. These results indicate that resveratrol generates cardioprotection by preconditioning the heart by HO-1-mediated mechanisms, which are regulated by p38MAP kinase and Akt survival signaling, but non-dependent on NFkappaB activation.
Das
Samarjit
S
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 6030-1110, USA. ddas@neuron.uchc.edu
Fraga
Cesar G
CG
Das
Dipak K
DK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009203:Myocardial Infarction / Q000201:enzymology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002316:Cardiotonic Agents; D051547:Heme Oxygenase-1; D008665:Metalloporphyrins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011524:Protoporphyrins; D000077185:Resveratrol; D013267:Stilbenes; D048051:p38 Mitogen-Activated Protein Kinases; C032628:tin protoporphyrin IX