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CARDIOVASCULAR

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

Department of Pharmacology and Centers for Vascular Biology and Connective Tissue Diseases, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

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 -1 and -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.

Address correspondence to: Dr. Kafait U. Malik, Professor of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Ave., #115 Crowe Bldg., Memphis, TN 38163. E-mail: kmalik{at}utmem.edu

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