Exp Mol Med.  2007 Jun;39(3):267-277.

Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells

• Pae HO
• Jeong GS
• Jeong SO
• Kim HS
• Kim SA
• Kim YC
• Yoo SJ
• Kim HD
• Chung HT

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.

Keyword

carbon monoxide; cell proliferation; curcumin; heme oxygenase-1; NF-E2-related factor 2; muscle, smooth, vascular

MeSH Terms

Active Transport, Cell Nucleus
Animals
Aorta/cytology
Cell Nucleus/metabolism
Cell Proliferation/*drug effects
Cells, Cultured
Curcumin/analogs & derivatives/*pharmacology
Cyclin-Dependent Kinase Inhibitor p21/biosynthesis/metabolism
Gene Expression Regulation
Heme Oxygenase (Decyclizing)/biosynthesis/genetics/*physiology
Heme Oxygenase-1/biosynthesis/genetics/*physiology
Humans
Metalloporphyrins/pharmacology
Muscle, Smooth, Vascular/drug effects/*physiology
Myocytes, Smooth Muscle/drug effects/*physiology
NF-E2-Related Factor 2/metabolism
Protoporphyrins/pharmacology
Rats
Regulatory Sequences, Nucleic Acid
Response Elements
Tumor Necrosis Factor-alpha/pharmacology