Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

Ahmad Boota, Bruce Johnson, Kee L. Lee, Michelle A. Blaskovich, Shang Xi Liu, Valerian E. Kagan, Andrew Hamilton, Bruce Pitt, Saïd M. Sebti, Paul Davies

Research output: Contribution to journalArticle

Abstract

We recently showed that the farnesyltransferase inhibitor FTI-277 blocks interleukin 1β (IL-1β)-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-1β 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-1β, 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume278
Issue number2 22-2
Publication statusPublished - Feb 2000

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Keywords

  • Farnesyltransferase
  • Geranylgeranyltransferase
  • Interleukin-β
  • Platelet-derived growth factor
  • Ras

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Boota, A., Johnson, B., Lee, K. L., Blaskovich, M. A., Liu, S. X., Kagan, V. E., ... Davies, P. (2000). Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology, 278(2 22-2).