Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells.
- Author:
Hyun Ock PAE
1
;
Gil Saeng JEONG
;
Sun Oh JEONG
;
Hak Sung KIM
;
Soon Ai KIM
;
Youn Chul KIM
;
Su Jin YOO
;
Heung Doo KIM
;
Hun Taeg CHUNG
Author Information
1. Medicinal Resources Research Institute, Wonkwang University, Iksan 570-749, Korea. htchung@wonkwang.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
carbon monoxide;
cell proliferation;
curcumin;
heme oxygenase-1;
NF-E2-related factor 2;
muscle, smooth, vascular
- MeSH:
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
- From:Experimental & Molecular Medicine
2007;39(3):267-277
- CountryRepublic of Korea
- Language:English
-
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.
