Abstract 5895: Resveratrol Modulates Estrogen Receptor-Rho GTPase Axis to Reduce Restenosis in a Mouse Carotid Artery Injury Model
Restenosis is a major clinical problem compromising the success of angioplasty. The underlying cause is neointimal hyperplasia resulting from migration to and proliferation of vascular smooth muscle cells (VSMC) within the intima of the vessel wall. Although restenosis is multifactorial, inhibition of VSMC proliferation significantly decreases neointimal hyperplasia. Resveratrol (RESV) is a red wine polyphenol that exhibits a wide array of vascular protective effects. Our hypothesis was that the anti-proliferative effects of RESV are mediated by a dual mechanism involving stimulation of the estrogen receptor (ER) and inhibition nuclear factor-kappa B (NF-κB) activation. To test this hypothesis and elucidate the underlying molecular mechanisms we investigated the effects of RESV on TNF-α stimulated VSMC proliferation. Our results indicate treatment with RESV significantly decreased inhibitory kappa kinase (IKK) activity and NF-κB activation. In addition to its effects on the NF-κB pathway, RESV also inhibited the Rho GTPase family member Rac-1 and its main downstream effector p21-activated kinase (PAK). Interestingly, these inhibitory effects of RESV were reversed by ICI 182,780, a selective estrogen receptor antagonist. Further, PAK activation was required for TNF-α induced NF-κB activation, suggesting Rac/PAK serves as an upstream regulator of NF-κB activation. To confirm these findings in vivo, we utilized the mouse carotid artery endothelial denudation model, a well established model used for studying restenosis. ER-α (−/−) and wildtype female mice were fed a high fat diet containing 50 mg/kg RESV for 2 weeks. The carotid artery denudation procedure was performed and the mice were again administered the high fat diet containing RESV for 2 weeks. Mice were sacrificed and the carotid arteries were excised. Our results indicate that RESV significantly decreased the restenotic index in the wildtype (WT) but not ER-α (−/−) mice (p<0.01). Further, RESV inhibited NF-κB activation and decreased the expression of activated PAK in injured arteries from WT but not ER-α (−/−) mice. In conclusion, our studies suggest that RESV reduces VSMC proliferation and inhibits restenosis via ER-α-dependent, Rac-1/pPAK/NF-κB mediated pathway.