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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
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Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

A Boota1, B Johnson, K L Lee

  • 1Department of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|February 9, 2000
PubMed

Insights

Farnesyltransferase and geranylgeranyltransferase inhibitors block superoxide production in pulmonary vascular smooth muscle cells, suggesting a therapeutic role in vascular injury.

Area of Science:

  • Vascular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Interleukin-1beta (IL-1beta) and platelet-derived growth factor (PDGF) influence vascular smooth muscle cell (SMC) function.
  • Nitric oxide (NO) production in pulmonary vascular SMC is modulated by farnesyltransferase inhibitor FTI-277 and geranylgeranyltransferase inhibitor GGTI-298.
  • The role of protein prenylation in oxidant radical generation by vascular SMC requires further elucidation.

Purpose of the Study:

  • To investigate the role of protein prenylation in IL-1beta and PDGF-induced superoxide production in pulmonary vascular SMC.
  • To identify the enzyme responsible for superoxide generation stimulated by IL-1beta, PDGF, and Ras.
  • To assess the potential therapeutic utility of FTI-277 and GGTI-298 in vascular conditions involving oxidant stress.

Main Methods:

  • Treatment of pulmonary vascular SMC with FTI-277 and GGTI-298.
  • Measurement of superoxide production stimulated by IL-1beta, PDGF, and constitutively active H-Ras.
  • Inhibition of superoxide production using diphenyleneiodonium.

Main Results:

  • Both FTI-277 and GGTI-298 blocked IL-1beta and PDGF-stimulated superoxide production in pulmonary vascular SMC.
  • FTI-277 and GGTI-298 also inhibited superoxide production stimulated by constitutively active H-Ras.
  • Diphenyleneiodonium blocked superoxide production, implicating NAD(P)H oxidase as the generating enzyme.

Conclusions:

  • Farnesylated and geranylgeranylated proteins are essential for superoxide production in pulmonary vascular SMC.
  • NAD(P)H oxidase is the primary enzyme responsible for this superoxide generation.
  • FTI-277 and GGTI-298 demonstrate potential therapeutic value by suppressing superoxide generation in inflammatory and mitogenic vascular responses.

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