OBJECTIVES: Resistin has a potential role in atherosclerosis because resistin produces proinflammatory effects in the vascular wall. However, the molecular mechanism of resistin increase in atherosclerosis remains unclear. Hypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cells functions. We sought to investigate the molecular regulation of resistin expression under hypoxia in cultured vascular smooth muscle cells. METHODS: Vascular smooth muscle cells from thoracic aorta of adult Wistar rats were cultured and subjected to hypoxia at 2.5% oxygen in a hypoxic chamber. Western blot, real-time PCR, reactive oxygen species assay, and promoter activity were measured. RESULTS: Hypoxia significantly increased the resistin protein (3.5-fold, P <0.001) and mRNA (4.8-fold, P <0.001) expression as compared with the control cells. The specific extracellular signal-regulated kinase (ERK) inhibitor PD98059, antioxidant N-acetylcysteine, and ERK siRNA attenuated the induction of resistin protein by hypoxia. It increased the phosphorylated ERK protein expression (3.2-fold, P <0.001), whereas pretreatment with PD98059 and N-acetylcysteine significantly blocked the increase of phosphorylated ERK by hypoxia. It also increased the reactive oxygen species production (9.3-fold, P <0.001), and pretreatment with N-acetylcysteine significantly blocked the induction of reactive oxygen species by hypoxia. Hypoxia increased resistin promoter activity (5.1-fold, P <0.001), and the activity was abolished when nuclear factor of activating T cells in the promoter area was mutated. Pretreatment with PD98059 and N-acetylcysteine significantly attenuated the resistin promoter activity induced by hypoxia. CONCLUSION: Hypoxia increases the resistin expression in cultured rat vascular smooth muscle cells under hypoxia. The hypoxia-induced resistin is mediated through reactive oxygen species, ERK mitogen-activated protein (MAP) kinase and nuclear factor of activating T cells pathway.
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