title: Inhibition of neointimal formation by trans-resveratrol: role of phosphatidyl inositol 3-kinase-dependent Nrf2 activation in heme oxygenase-1 induction.
abstract: Neointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitory effects on proliferation and migration of vascular smooth muscle cells has been reported, its activity on neointimal formation is still unclear. Oral administration of trans-resveratrol significantly suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. In cultured vascular smooth muscle cells, trans-resveratrol inhibited platelet-derived growth factor-stimulated DNA synthesis and cell proliferation with down-regulation of cyclin D and pRB. Moreover, platelet-derived growth factor-induced production of reactive oxygen species was inhibited by trans-resveratrol and the compound induced heme oxygenase-1 (HO-1). The anti-proliferative activity of trans-resveratrol was reversed by an HO-1 inhibitor, ZnPPIX. Subcellular fractionation and reporter gene analyses revealed that trans-resveratrol increased the level of nuclear Nrf2 and antioxidant response element reporter activity, and that these were essential for the induction of HO-1. Trans-resveratrol also enhanced the activities of phosphatidyl inositol 3-kinase and extracellular signal regulated kinase, and phosphatidyl inositol 3-kinase was required for Nrf2/antioxidant response element-dependent HO-1 induction. These data have significant implications for the elucidation of the pharmacological mechanism by which trans-resveratrol prevents vascular occlusive diseases.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Moo Yeol
authors.initials: MY
authors.lastname: Lee
authors.forename: Jeong Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006965:Hyperplasia / Q000517:prevention & control; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D058426:Neointima / Q000473:pathology / Q000517:prevention & control*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D056741:Cyclin D; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D013267:Stilbenes; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D000077185:Resveratrol