Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

被引:104
作者
Davis, BB
Thompson, DA
Howard, LL
Morisseau, C
Hammock, BD
Weiss, RH
机构
[1] Univ Calif Davis, Dept Internal Med, Div Nephrol, Davis, CA 95616 USA
[2] Univ Calif Davis, Cell & Dev Biol Grad Grp, Davis, CA 95616 USA
[3] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA
[4] Univ Calif Davis, Canc Res Ctr, Davis, CA 95616 USA
[5] Dept Vet Affairs No Calif Hlth Care Syst, Mather, CA 95655 USA
关键词
D O I
10.1073/pnas.261710799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Atherosclerosis, in its myriad incarnations the foremost killer disease in the industrialized world, is characterized by aberrant proliferation of vascular smooth muscle (VSM) cells in part as a result of the recruitment of inflammatory cells to the blood vessel wall. The epoxyeicosatrienoic acids are synthesized from arachidonic acid in a reaction catalyzed by the cytochrome P450 system and are vasoactive substances. Metabolism of these compounds by epoxide hydrolases results in the formation of compounds that affect the vasculature in a pleiotropic manner. As an outgrowth of our observations that urea inhibitors of the soluble epoxide hydrolase (sEH) reduce blood pressure in spontaneously hypertensive rats as well as the findings of other investigators that these compounds possess antiinflammatory actions, we have examined the effect of sEH inhibitors on VSM cell proliferation. We now show that the sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) inhibits human VSM cell proliferation in a dose-dependent manner and is associated with a decrease in the level of cyclin D1. In addition, cis-epoxyeicosatrienoic acid mimics the growth-suppressive activity of CDU; there is no evidence of cellular toxicity or apoptosis in CDU-treated cells when incubated with 20 muM CDU for up to 48 h. These results, in light of the antiinflammatory and antihypertensive properties of these compounds that have been demonstrated already, suggest that the urea class of sEH inhibitors may be useful for therapy for diseases such as hypertension and atherosclerosis characterized by exuberant VSM cell proliferation and vascular inflammation.
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收藏
页码:2222 / 2227
页数:6
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