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Inhibition of neointimal formation by trans ‐resveratrol: Role of phosphatidyl inositol 3‐kinase‐dependent Nrf2 activation in heme oxygenase‐1 induction
Author(s) -
Kim Jung Woo,
Lim Sung Chul,
Lee Moo Yeol,
Lee Jeong Woon,
Oh Won Keun,
Kim Sang Kyum,
Kang Keon Wook
Publication year - 2010
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201000016
Subject(s) - resveratrol , heme oxygenase , chemistry , vascular smooth muscle , neointimal hyperplasia , kinase , microbiology and biotechnology , biochemistry , pharmacology , biology , endocrinology , medicine , heme , enzyme , restenosis , smooth muscle , stent
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.