(Hypertension. 1998;31:242.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Cytochrome P-450 Metabolites Mediate Norepinephrine-Induced Mitogenic Signaling
From the Department of Pharmacology, College of Medicine, The University of Tennessee Center for Health Sciences (M.M.M. and K.U.M.), Southern College of Optometry (N.A.K. and I.F.B.), and LeMoyne Owen College (M.R.U.), Memphis, Tenn.
Correspondence to Kafait U. Malik, DSc, PhD, Professor, Department of Pharmacology, College of Medicine. The University of Tennessee, The Health Science Center, Memphis, TN 38163. E-mail kmalik{at}utmem1.utmem.edu
Norepinephrine (NE) stimulates release of arachidonic acid (AA) from tissue lipids in blood vessels, which is metabolized via cyclooxygenase, lipoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to biologically active products. Moreover, NE and AA have been shown to stimulate proliferation of vascular smooth muscle cells (VSMCs) of rat aorta. The purpose of this study was to determine the possible contribution of AA and its metabolites to NE-induced mitogenesis in VSMCs of rat aorta and the underlying mechanism of their actions. NE (0.1 to 10 µmol/L) increased DNA synthesis as measured by [3H]thymidine incorporation in VSMCs, and this effect was attenuated by inhibitors of CYP-450 (17-octadecynoic acid, 5 µmol/L; 12-diabromododec-11-enoic acid, 10 µmol/L; and dibromo-dodecenyl-methylsulfimide, 10 µmol/L) and by the LO inhibitor (baicalein, 20 µmol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 µmol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to fimide, 10 µmol/L) and by the LO inhibitor (baicalein, 20 µmol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 µmol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to 0.5 µmol/L) and 12(S)-HETE, respectively, increased [3H]thymidine incorporation in VSMCs. Both NE and 20-HETE increased mitogen activated protein (MAP) kinase activity as measured by the in-gel kinase assay. The inhibitor of MAP kinase kinase, PD-98059 (50 µmol/L), attenuated NE as well as 20-HETE induced [3H]thymidine incorporation and MAP kinase activation in VSMCs. These data suggest that products of AA formed via CYP-450, most likely 20-HETE, and via LO mediate NE induced mitogenesis in VSMCs.
Key Words: vascular smooth muscle cells • mitogenesis • 20-hydroxyeicosatetraenoic acid • norepinephrine • MAP kinase • proliferation
Abbreviations: AA = arachidonic acid • BACL = baicalein • COX = cyclooxygenase • cPLA2 = cytosolic phospholipase A2 • CYP-450 = cytochrome P-450 • DBDD = 12-dibromododec-11-enoic acid • DDMS = dibromo-dodecenyl-methylsulfimide • ERK = extracellular regulated kinase • FBS = fetal bovine serum • HETE = hydroxyeicosatetraenoic acid • IND = indomethacin; • LO = lipoxygenase • MAFP = methyl arachidonyl fluoro phosphonate; MAP kinase mitogen activated protein kinase • MEK = MAP kinase kinase; MBP, myelin basic protein • NE = norepinephrine • 17-ODYA = 17-octadecynoic acid; TBS, tris-buffer saline • VSMC = vascular smooth muscle cell
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