Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor alpha-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 (PPARalpha) and the role of PPARalpha in smooth muscle cell proliferation. METHODS AND RESULTS Alkanoic acids transactivated PPARalpha, induced binding of PPARalpha to its response element, and significantly induced the expression of PPARalpha-responsive genes, showing their function as PPARalpha 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 PPARalpha expression, it was determined that PPARalpha 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 PPARalpha. These acids may be useful for designing therapeutics to treat diseases characterized by excessive smooth muscle cell proliferation.