Abstract
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 p21(WAF1/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 p21(WAF1/CIP1). Inhibition of VSMC growth and expression of p21(WAF1/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-alpha and increased p21(WAF1/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.
Highlights
Vascular smooth muscle cells (VSMCs) comprise the major cellular component of the normal arterial wall and the excessive growth of VSMCs is a key abnormality in the development of atherosclerosis lesions and restenosis after balloon angioplasty (Sata, 2006)
Despite displaying a similar basic chemical structure, the metabolite tetrahydrocurcumin did not induce heme oxygenase-1 (HO-1) expression even at higher concentrations (Figure 2C)
We found that curcumin induced HO-1 expression and HO activity in a dose-dependent manner (Figure 2)
Summary
Vascular smooth muscle cells (VSMCs) comprise the major cellular component of the normal arterial wall and the excessive growth of VSMCs is a key abnormality in the development of atherosclerosis lesions and restenosis after balloon angioplasty (Sata, 2006). Inhibition of VSMC proliferation represents an important therapeutic strategy for treatment of these diseases. VSMCs from HO-1-deficient mice display abnormal growth (Yet et al, 2003). Over-expression of HO-1 by either transfection of the HO-1 gene or exogenous administration of a certain HO-1 inducer reduces excessive VSMC proliferation (Juan et al, 2001). Genetic approaches targeting HO-1 or pharmacological interventions using HO-1 inducers may offer a promising therapeutic modality in treating occlusive vascular disease
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