title: Activation of mitogen-activated protein kinases by arachidonic acid and its metabolites in vascular smooth muscle cells.
abstract: Previous studies from this laboratory and others suggest that arachidonic acid and its metabolites play important roles in a variety of biological processes such as signal transduction, contraction, chemotaxis, and cell growth and differentiation. Here we studied the effect of arachidonic acid on mitogen-activated protein (MAP) kinases in vascular smooth muscle cells (VSMC). Arachidonic acid activated MAP kinases in VSMC in a time- and dose-dependent manner. Nordihydroguaiaretic acid (NDGA), a potent inhibitor of the lipoxygenase system, significantly blocked the arachidonic acid-induced activation of MAP kinases, whereas indomethacin, an inhibitor of cyclooxygenase, had no effect. In VSMC, arachidonic acid was converted to 15-hydroxyeicosatetraenoic acid (15-HETE); NDGA inhibited the formation of this HETE. Exogenous addition of 15-HETE to VSMC caused stimulation of MAP kinases. Depletion of protein kinase C attenuated both the arachidonic acid- and 15-HETE-induced activation of MAP kinases in VSMC. Together these results suggest that 1) arachidonic acid activates MAP kinases in VSMC; 2) 15-HETE, a 15-lipoxygenase product of arachidonic acid, at least in part, mediates the arachidonic acid effect on MAP kinases; and 3) protein kinase C appears to be important in arachidonic acid activation of MAP kinases. Therefore, MAP kinases may play an important role in arachidonic acid signaling of VSMC growth and function.
authors.affiliation: Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: G N
authors.initials: GN
authors.lastname: Rao
authors.forename: A S
authors.initials: AS
authors.lastname: Baas
authors.forename: W C
authors.initials: WC
authors.lastname: Glasgow
authors.forename: T E
authors.initials: TE
authors.lastname: Eling
authors.forename: M S
authors.initials: MS
authors.lastname: Runge
authors.forename: R W
authors.initials: RW
authors.lastname: Alexander
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D015237:Dinoprost; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D015232:Dinoprostone