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In vascular smooth muscle cells (VSMCs), inductionof the heme oxygenase-1 (HO-1) confers vascularprotection against cellular proliferation mainly viaits up-regulation of the cyclin-dependent kinaseinhibitor p21WAF1/CIP1 that is involved in negativeregulation of cellular proliferation. In the presentstudy, we investigated whether the phytochemicalcurcumin and its metabolite tetrahydrocurcumincould induce HO-1 expression and growth inhibitionin rat VSMCs and, if so, whether their antiproliferativeeffect could be mediated via HO-1 expression. Atnon-toxic concentrations, curcumin possessingtwo Michael-reaction acceptors induced HO-1 expressionby activating antioxidant response element(ARE) through translocation of the nuclear transcriptionfactor E2-related factor-2 (Nrf2) into thenucleus and also inhibited VSMC growth triggeredby 5% FBS in a dose-dependent manner. In contrast,tetrahydrocurcumin lacking Michael-reaction accep -tor showed no effect on HO-1 expression, AREactivation and VSMC growth inhibition. The antiproliferativeeffect of curcumin in VSMCs was accompaniedby the increased expression of p21WAF1/CIP1. Inhibition of VSMC growth and expression ofp21WAF1/CIP1by curcumin were partially, but notcompletely, abolished when the cells were coincubatedwith the HO inhibitor tin protoporphyrin. In human aortic smooth muscle cells (HASMCs),curcumin also inhibited growth triggered by TNF-αand increased p21WAF1/CIP1expression via HO-1-dependent manner. Our findings suggest that curcuminhas an ability to induce HO-1 expression,presumably through Nrf2-dependent ARE activation,in rat VSMCs and HASMCs, and provide evidence thatthe antiproliferative effect of curcumin is considerablylinked to its ability to induce HO-1 expression.

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