Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Benjamin B. Davis, David A. Thompson, Laura L. Howard, Christophe Morisseau, Bruce D. Hammock, Robert H Weiss

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

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 dosedependent manner and is associated with a decrease in the level of cyclin D1. In addition, cis-epoxyeicosatrienoic acid mimics the growthn suppressive activity of CDU; there is no evidence of cellular toxicity or apoptosis in CDU-treated cells when incubated with 20 μM 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.

Original languageEnglish (US)
Pages (from-to)2222-2227
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number4
DOIs
StatePublished - Feb 19 2002

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Epoxide Hydrolases
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Proliferation
NSC 153174
Blood Vessels
Urea
Atherosclerosis
Anti-Inflammatory Agents
Cyclin D1
Inbred SHR Rats
Arachidonic Acid
Cytochrome P-450 Enzyme System
Antihypertensive Agents
Research Personnel
Apoptosis
Blood Pressure
Hypertension
Inflammation
Acids

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. / Davis, Benjamin B.; Thompson, David A.; Howard, Laura L.; Morisseau, Christophe; Hammock, Bruce D.; Weiss, Robert H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 4, 19.02.2002, p. 2222-2227.

Research output: Contribution to journalArticle

Davis, Benjamin B. ; Thompson, David A. ; Howard, Laura L. ; Morisseau, Christophe ; Hammock, Bruce D. ; Weiss, Robert H. / Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 4. pp. 2222-2227.
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