Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells.
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.
Pae
Hyun-Ock
HO
Medicinal Resources Research Institute, Department of Microbiology and Immunology, Wonkwang University, Iksan 570-749, Korea.
Jeong
Gil-Saeng
GS
Jeong
Sun-Oh
SO
Kim
Hak Sung
HS
Kim
Soon-Ai
SA
Kim
Youn-Chul
YC
Yoo
Su-Jin
SJ
Kim
Heung-Doo
HD
Chung
Hun-Taeg
HT
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001011:Aorta / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism; D005786:Gene Expression Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D020218:Response Elements; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008665:Metalloporphyrins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011524:Protoporphyrins; D014409:Tumor Necrosis Factor-alpha; C096277:tetrahydrocurcumin; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C491523:Hmox1 protein, rat; D003474:Curcumin