Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor α-dependent repression of cyclin D1

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 alpha ( PPAR alpha) and the role of PPAR alpha in smooth muscle cell proliferation. Methods and Results - Alkanoic acids transactivated PPAR alpha, induced binding of PPAR alpha to its response element, and significantly induced the expression of PPAR alpha- responsive genes, showing their function as PPAR alpha 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 alpha expression, it was determined that PPAR alpha 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 alpha. These acids may be useful for designing therapeutics to treat diseases characterized by excessive smooth muscle cell proliferation.