Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB

Free Radic Res. 2006 Oct;40(10):1066-75. doi: 10.1080/10715760600833085.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Retracted Publication

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cardiotonic Agents / pharmacology*
  • Heart / drug effects
  • Heme Oxygenase-1 / metabolism*
  • In Vitro Techniques
  • Ischemic Preconditioning, Myocardial
  • Male
  • Metalloporphyrins / pharmacology
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / enzymology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protoporphyrins / pharmacology
  • Rats
  • Resveratrol
  • Signal Transduction / drug effects*
  • Stilbenes / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cardiotonic Agents
  • Metalloporphyrins
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Protoporphyrins
  • Stilbenes
  • tin protoporphyrin IX
  • Heme Oxygenase-1
  • p38 Mitogen-Activated Protein Kinases
  • Resveratrol