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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2462.)
© 2006 American Heart Association, Inc.

Vascular Biology

Inhibition of Smooth Muscle Proliferation by Urea-Based Alkanoic Acids via Peroxisome Proliferator-Activated Receptor –Dependent Repression of Cyclin D1

Valerie Y. Ng; Christophe Morisseau; John R. Falck; Bruce D. Hammock; Deanna L. Kroetz

From the Department of Biopharmaceutical Sciences (V.Y.N., D.L.K.), the Center for Human Genetics (D.L.K.), and the Liver Center (D.L.K.), University of California, San Francisco; Department of Entomology and the Cancer Research Center (C.M., B.D.H), University of California, Davis; and Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas.

Correspondence to Deanna L. Kroetz, PhD, Department of Biopharmaceutical Sciences, University of California San Francisco, 1550 4th St, Box 2911, San Francisco, CA 94143-2911. E-mail deanna.kroetz{at}ucsf.edu

Objective— Proliferation of smooth muscle cells is implicated in cardiovascular complications. Previously, a urea-based soluble epoxide hydrolase inhibitor was shown to attenuate smooth muscle cell proliferation. We examined the possibility that urea-based alkanoic acids activate the nuclear receptor peroxisome proliferator-activated receptor (PPAR) and the role of PPAR in smooth muscle cell proliferation.

Methods and Results— Alkanoic acids transactivated PPAR, induced binding of PPAR to its response element, and significantly induced the expression of PPAR-responsive genes, showing their function as PPAR agonists. Furthermore, the alkanoic acids attenuated platelet-derived growth factor–induced smooth muscle cell proliferation via repression of cyclin D1 expression. Using small interfering RNA to decrease endogenous PPAR expression, it was determined that PPAR was partially involved in the cyclin D1 repression. The antiproliferative effects of alkanoic acids may also be attributed to their inhibitory effects on soluble epoxide hydrolase, because epoxyeicosatrienoic acids alone inhibited smooth muscle cell proliferation.

Conclusions— These results show that attenuation of smooth muscle cell proliferation by urea-based alkanoic acids is mediated, in part, by the activation of PPAR. These acids may be useful for designing therapeutics to treat diseases characterized by excessive smooth muscle cell proliferation.

Proliferation of smooth muscle cells is implicated in cardiovascular complications. Urea-based alkanoic acids are identified as agonists of the nuclear receptor peroxisome proliferator-activated receptor (PPAR). These acids attenuate smooth muscle cell proliferation, in part by decreasing cyclin D1 via PPAR activation.

Key Words: soluble expoxide hydrolase • epoxyeicosatrienoic acids • PPAR • smooth muscle cells • proliferation

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