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Journal of Lipid Research, Vol. 49, 66-73, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

20-HETE inhibits the proliferation of vascular smooth muscle cells via transforming growth factor-β

Chan-Jung Liang^*, Harlan E. Ives, Chuen-Mao Yang^* and Yunn-Hwa Ma^1,*

^* Department of Physiology and Pharmacology, Center for Healthy Aging Research, Chang Gung University, Kuei-Shan, Tao-Yuan, Taiwan ROC
Department of Medicine, Division of Nephrology, University of California, San Francisco, CA

Published, JLR Papers in Press, October 4, 2007.

¹ To whom correspondence should be addressed. e-mail: yhma{at}mail.cgu.edu.tw

20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 arachidonic acid metabolite, has been shown to modulate the growth of vascular smooth muscle cells (VSMCs). We asked whether 20-HETE modulates the proliferation of R22D cells, a clonal VSMC from neonatal rats, by releasing transforming growth factor-β (TGF-β). Incubation of R22D cells with 20-HETE for 24 h attenuated [³H]thymidine incorporation in a concentration-dependent manner without causing the release of lactate dehydrogenase. 20-HETE also inhibited platelet-derived growth factor (PDGF)-induced [³H]thymidine incorporation in R22D cells and human VSMCs. At 5 µM, 20-HETE reduced [³H]thymidine incorporation by 34 ± 6%; anti-TGF-β neutralizing antibody, but not nonspecific IgG, completely reversed the attenuated [³H]thymidine incorporation induced by 20-HETE. In addition, 20-HETE attenuated fetal bovine serum- and PDGF-induced expression of cyclin D1, a downstream effector of TGF-β₁, which was reversed by anti-TGF-β antibody. Further studies demonstrated that 20-HETE may increase TGF-β release to a level high enough to inhibit [³H]thymidine incorporation without altering the steady-state mRNA level of TGF-β. Nevertheless, pretreatment of indomethacin (a cyclooxygenase inhibitor) or paxilline (a potassium channel inhibitor) did not affect the inhibitory effect on DNA synthesis induced by 20-HETE. These results demonstrate for the first time a growth-inhibitory effect induced by 20-HETE, which may be mediated by TGF-β.

Supplementary key words 20-hydroxyeicosatetraenoic acid • cytochrome P450 • platelet-derived growth factor • DNA synthesis

Abbreviations: CDK, cyclin-dependent kinase; ECM, extracellular matrix; EPA, eicosapentaenoic acid; ERK 1/2, extracellular regulated protein kinase 1/2; FBS, fetal bovine serum; 20-HETE, 20-hydroxyeicosatetraenoic acid; LDH, lactate dehydrogenase; LTBP, latent TGF binding protein; MEK, MAPK/ERK kinase; MMP, matrix metalloprotease; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VSMC, vascular smooth muscle cell

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