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KMID : 0620920070390030267
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Experimental & Molecular Medicine
2007 Volume.39 No. 3 p.267 ~ p.277
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Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells
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Pae Hyun-Ock
Jeong Gil-Saeng
Jeong Sun-Oh
Kim Hak-Sung
Kim Soon-Ai
Kim Youn-Chul
Yoo Su-Jin
Kim Heung-Doo
Chung Hun-Taeg
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Abstract
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In vascular smooth muscle cells (VSMCs), induction of the heme oxygenase-1 (HO-1) confers vascular protection against cellular proliferation mainly via its up-regulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 that is involved in negative regulation of cellular proliferation. In the present study, we investigated whether the phytochemical curcumin and its metabolite tetrahydrocurcumin could induce HO-1 expression and growth inhibition in rat VSMCs and, if so, whether their antiproliferative effect could be mediated via HO-1 expression. At non-toxic concentrations, curcumin possessing two Michael-reaction acceptors induced HO-1 expression by activating antioxidant response element (ARE) through translocation of the nuclear transcription factor E2-related factor-2 (Nrf2) into the nucleus and also inhibited VSMC growth triggered by 5% FBS in a dose-dependent manner. In contrast, tetrahydrocurcumin lacking Michael-reaction acceptor showed no effect on HO-1 expression, ARE activation and VSMC growth inhibition. The antiproliferative effect of curcumin in VSMCs was accompanied by the increased expression of p21WAF1/CIP1. Inhibition of VSMC growth and expression of p21WAF1/CIP1 by curcumin were partially, but not completely, abolished when the cells were co- incubated with the HO inhibitor tin protoporphyrin. In human aortic smooth muscle cells (HASMCs), curcumin also inhibited growth triggered by TNF-a and increased p21WAF1/CIP1 expression via HO-1- dependent manner. Our findings suggest that curcumin has an ability to induce HO-1 expression, presumably through Nrf2-dependent ARE activation, in rat VSMCs and HASMCs, and provide evidence that the antiproliferative effect of curcumin is considerably linked to its ability to induce HO-1 expression.
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KEYWORD
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carbon monoxide, cell proliferation, curcumin, heme oxygenase-1, NF-E2-related factor 2, muscle, smooth, vascular
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