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Am J Physiol Lung Cell Mol Physiol 278: L329-L334, 2000;
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Vol. 278, Issue 2, L329-L334, February 2000

Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

Ahmad Boota1, Bruce Johnson1, Kee-L Lee2, Michelle A. Blaskovich3,4, Shang-Xi Liu5, Valerian E. Kagan5, Andrew Hamilton2, Bruce Pitt3, Saïd M. Sebti3,4, and Paul Davies3

Departments of 3 Pharmacology, 2 Chemistry, 1 Pulmonary, Allergy and Critical Care Medicine, and 5 Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and 4 Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, and Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612

We recently showed that the farnesyltransferase inhibitor FTI-277 blocks interleukin 1beta (IL-1beta )-induced nitric oxide production in pulmonary vascular smooth muscle cells (SMC), whereas the geranylgeranyltransferase inhibitor GGTI-298 enhances this effect. Here we show that IL-1beta and platelet-derived growth factor (PDGF) stimulate superoxide production by pulmonary vascular SMC and that this effect is blocked by both FTI-277 and GGTI-298, suggesting that farnesylated and geranylgeranylated proteins are required for superoxide production. We also show that FTI-277 and GGTI-298 block superoxide production stimulated by constitutively active mutant H-Ras. Furthermore, superoxide production by IL-1beta , PDGF factor, and constitutively activated Ras is blocked by diphenyleneiodonium, implicating NAD(P)H oxidase as the generating enzyme. Given the role of oxidant radicals in vascular reactivity and injury, the action of both FTI-277 and GGTI-298 in suppressing superoxide generation by an inflammatory cytokine as well as by a potent smooth muscle mitogen may be therapeutically useful.

farnesyltransferase; geranylgeranyltransferase; Ras; platelet-derived growth factor; interleukin-beta


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