Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

We recently showed that the farnesyltransferase inhibitor FTI-277 blocks in terleukin 1 beta (IL-1 beta)-induced nitric oxide production in pulmonary v ascular smooth muscle cells (SMC), whereas the geranylgeranyltransferase in hibitor GGTI-298 enhances this effect. Here we show that IL-1 beta and plat elet-derived growth factor (PDGF) stimulate superoxide production by pulmon ary vascular SMC and that this effect is blocked by both FTI-277 and GGTI-2 98, suggesting that farnesylated and geranylgeranylated proteins are requir ed for superoxide production. We also show that FTI-277 and GGTI-298 block superoxide production stimulated by constitutively active mutant H-Ras. Fur thermore, superoxide production by IL-1 beta, PDGF factor, and constitutive ly activated Ras is blocked by diphenyleneiodonium, implicating NAD(P)H oxi dase as the generating enzyme. Given the role of oxidant radicals in vascul ar reactivity and injury, the action of both FTI-277 and GGTI-298 in suppre ssing superoxide generation by an inflammatory cytokine as well as by a pot ent smooth muscle mitogen may be therapeutically useful.