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

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

Physiology and Pharmacology, Chang Gung University, Tao-Yuan 333

Corresponding Author: yhma{at}mail.cgu.edu.tw

20-hydroxyeicosatetraenoic acid (20-HETE), a P450 arachidonic acid metabolite, has been shown to modulate growth of vascular smooth muscle cells (VSMC). We asked whether 20-HETE modulates proliferation of R22D cell, a clonal VSMC from neonatal rats, via releasing TGF-ß. Incubation of R22D cells with 20-HETE for 24 hr attenuated [3H]-thymidine incorporation in a concentration-dependent manner without causing release of lactate dehydrogenase. 20-HETE also inhibited platelet-derived growth factor (PDGF)-induced [3H]-thymidine incorporation in R22D cells and human VSMC. At 5 µM, 20-HETE reduced [3H]-thymidine incorporation by 34 ± 6%; anti-TGF-ß 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-ß1, which was reversed by anti-TGF-ß antibody. Further studies demonstrated that 20-HETE may increase TGF-ß release to a level enough to inhibit [3H]-thymidine incorporation without altering steady state mRNA level of TGF-ß. 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 first demonstrate a growth inhibitory effect induced by 20-HETE, which may be mediated by TGF-ß.

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