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Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle
1Department of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
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.
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.