Small GTP binding protein Ras contributes to norepinephrine-induced mitogenesis of vascular smooth muscle cells

Mubarack M. Muthalif, Mohammed R. Uddin, Soghra Fatima, Jean Hugues Parmentier, Zinat Khandekar, Kafait U. Malik

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Norepinephrine stimulates release of arachidonic acid from tissue lipids. Arachidonic acid metabolites generated through the lipoxygenase and cytochrome P-450 pathways but not cyclooxygenase stimulate mitogen activated protein (MAP) kinase activity and proliferation of vascular smooth muscle cells (VSMC). Moreover, norepinephrine has been shown to activate the Ras/MAP kinase pathway through generation of cytochrome P-450 metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE). The purpose of this study was to investigate the contribution of Ras in norepinephrine-induced mitogenesis in aortic VSMC. Farnesylation of Ras by farnesyl transferase is required for its full activation. Norepinephrine-induced DNA synthesis, as measured by [3H]-thymidine incorporation, was attenuated by inhibitors of Ras farnesyl transferase FPT III and BMS-191563. These agents also inhibited 20-HETE-stimulated [3H]-thymidine incorporation. In cells transiently transfected with dominant negative Ras (RasN17), norepinephrine, and 20-HETE-induced proliferation of VSMC was attenuated. Both norepinephrine and 20-HETE increased localization of Ras to plasma membrane and MAP kinase activity; FPT III attenuated these effects. These data suggest that VSMC proliferation induced by norepinephrine and 20-HETE is mediated by Ras/MAP kinase pathway.

Original languageEnglish (US)
Pages (from-to)33-43
Number of pages11
JournalProstaglandins and Other Lipid Mediators
Volume65
Issue number1
DOIs
StatePublished - May 8 2001

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Vascular Smooth Muscle
GTP-Binding Proteins
Smooth Muscle Myocytes
Muscle
Norepinephrine
Cells
Mitogen-Activated Protein Kinases
Arachidonic Acid
Transferases
Metabolites
Thymidine
Cytochrome P-450 Enzyme System
Prenylation
Lipoxygenase
Cell proliferation
Cell membranes
Prostaglandin-Endoperoxide Synthases
Chemical activation
Cell Proliferation
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

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Small GTP binding protein Ras contributes to norepinephrine-induced mitogenesis of vascular smooth muscle cells. / Muthalif, Mubarack M.; Uddin, Mohammed R.; Fatima, Soghra; Parmentier, Jean Hugues; Khandekar, Zinat; Malik, Kafait U.

In: Prostaglandins and Other Lipid Mediators, Vol. 65, No. 1, 08.05.2001, p. 33-43.

Research output: Contribution to journalArticle

Muthalif, Mubarack M. ; Uddin, Mohammed R. ; Fatima, Soghra ; Parmentier, Jean Hugues ; Khandekar, Zinat ; Malik, Kafait U. / Small GTP binding protein Ras contributes to norepinephrine-induced mitogenesis of vascular smooth muscle cells. In: Prostaglandins and Other Lipid Mediators. 2001 ; Vol. 65, No. 1. pp. 33-43.
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