Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A2 in vascular smooth muscle cells

Shailaja Kalyankrishna, Kafait Malik

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Abstract

p38 mitogen-activated protein kinase (MAPK) is activated by norepinephrine (NE) in the vasculature and is implicated in vascular smooth muscle hypertrophy, contraction, and cell migration. NE promotes influx of Ca2+ and activates cytosolic phospholipase A2 (cPLA2) in vascular smooth muscle cells (VSMC). The purpose of this study was to determine the contribution of cPLA2-generated arachidonic acid (AA) and its metabolites to the activation of p38 MAPK measured by its phosphorylation, in response to NE in rabbit VSMC. NE-induced p38 MAPK activation was found to be mediated through the stimulation of α-1 and α-2 adrenergic receptors, was dependent on extracellular Ca2+, and was attenuated by an inhibitor of cPLA2 (pyrrolidine-1). Moreover, the cPLA2 product, AA, activated p38 MAPK in VSMC. p38 MAPK activation elicited by NE was decreased significantly by the lipoxygenase (LO) inhibitor baicalein, and to a lesser extent by the cytochrome P450 inhibitor 17-octadecynoic acid, but was not affected by the cyclooxygenase inhibitor indomethacin. The LO metabolites of AA, namely 5(S)-hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, and 15(S)-HETE and the cytochrome P450 metabolite 20-HETE, activated p38 MAPK. NE-induced p38 MAPK stimulation was found to be independent of phospholipase D (PLD) activation in rabbit VSMC. Transactivation of the epidermal growth factor receptor (EGFR) by NE also did not contribute to p38 MAPK activation. These data suggest that cPLA2-generated AA and its LO metabolites mediate NE-induced p38 MAPK stimulation in rabbit VSMC by a mechanism that is independent of PLD and EGFR activation.

Original languageEnglish (US)
Pages (from-to)761-772
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number2
DOIs
StatePublished - Feb 1 2003

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Cytosolic Phospholipases A2
p38 Mitogen-Activated Protein Kinases
Vascular Smooth Muscle
Arachidonic Acid
Smooth Muscle Myocytes
Norepinephrine
Arachidonate Lipoxygenases
Phospholipase D
Rabbits
Epidermal Growth Factor Receptor
Cytochrome P-450 Enzyme System
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Hydroxyeicosatetraenoic Acids
Lipoxygenase Inhibitors
Cyclooxygenase Inhibitors
Muscle Contraction
Indomethacin
Adrenergic Receptors
Muscle Cells
Hypertrophy

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A2 in vascular smooth muscle cells",
abstract = "p38 mitogen-activated protein kinase (MAPK) is activated by norepinephrine (NE) in the vasculature and is implicated in vascular smooth muscle hypertrophy, contraction, and cell migration. NE promotes influx of Ca2+ and activates cytosolic phospholipase A2 (cPLA2) in vascular smooth muscle cells (VSMC). The purpose of this study was to determine the contribution of cPLA2-generated arachidonic acid (AA) and its metabolites to the activation of p38 MAPK measured by its phosphorylation, in response to NE in rabbit VSMC. NE-induced p38 MAPK activation was found to be mediated through the stimulation of α-1 and α-2 adrenergic receptors, was dependent on extracellular Ca2+, and was attenuated by an inhibitor of cPLA2 (pyrrolidine-1). Moreover, the cPLA2 product, AA, activated p38 MAPK in VSMC. p38 MAPK activation elicited by NE was decreased significantly by the lipoxygenase (LO) inhibitor baicalein, and to a lesser extent by the cytochrome P450 inhibitor 17-octadecynoic acid, but was not affected by the cyclooxygenase inhibitor indomethacin. The LO metabolites of AA, namely 5(S)-hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, and 15(S)-HETE and the cytochrome P450 metabolite 20-HETE, activated p38 MAPK. NE-induced p38 MAPK stimulation was found to be independent of phospholipase D (PLD) activation in rabbit VSMC. Transactivation of the epidermal growth factor receptor (EGFR) by NE also did not contribute to p38 MAPK activation. These data suggest that cPLA2-generated AA and its LO metabolites mediate NE-induced p38 MAPK stimulation in rabbit VSMC by a mechanism that is independent of PLD and EGFR activation.",
author = "Shailaja Kalyankrishna and Kafait Malik",
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AU - Malik, Kafait

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AB - p38 mitogen-activated protein kinase (MAPK) is activated by norepinephrine (NE) in the vasculature and is implicated in vascular smooth muscle hypertrophy, contraction, and cell migration. NE promotes influx of Ca2+ and activates cytosolic phospholipase A2 (cPLA2) in vascular smooth muscle cells (VSMC). The purpose of this study was to determine the contribution of cPLA2-generated arachidonic acid (AA) and its metabolites to the activation of p38 MAPK measured by its phosphorylation, in response to NE in rabbit VSMC. NE-induced p38 MAPK activation was found to be mediated through the stimulation of α-1 and α-2 adrenergic receptors, was dependent on extracellular Ca2+, and was attenuated by an inhibitor of cPLA2 (pyrrolidine-1). Moreover, the cPLA2 product, AA, activated p38 MAPK in VSMC. p38 MAPK activation elicited by NE was decreased significantly by the lipoxygenase (LO) inhibitor baicalein, and to a lesser extent by the cytochrome P450 inhibitor 17-octadecynoic acid, but was not affected by the cyclooxygenase inhibitor indomethacin. The LO metabolites of AA, namely 5(S)-hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, and 15(S)-HETE and the cytochrome P450 metabolite 20-HETE, activated p38 MAPK. NE-induced p38 MAPK stimulation was found to be independent of phospholipase D (PLD) activation in rabbit VSMC. Transactivation of the epidermal growth factor receptor (EGFR) by NE also did not contribute to p38 MAPK activation. These data suggest that cPLA2-generated AA and its LO metabolites mediate NE-induced p38 MAPK stimulation in rabbit VSMC by a mechanism that is independent of PLD and EGFR activation.

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