Endothelin-1 induced vascular smooth muscle cell proliferation is mediated by cytochrome p-450 arachidonic acid metabolites.
Endothelins (ETs) are a family of three peptides (ET-1, ET-2, ET-3) that are implicated in the physiological control of vascular smooth muscle cell (VSMC) and myocardial contractility and growth. ET-1 is vasoactive peptide that acts via ET-A receptors coupling inducing vascular smooth muscle cell contraction. ET-1 is involved in the development and maintenance of hypertension. Aim of this study was to investigate whether ET-1 can induce vascular smooth muscle cell proliferation through arachidonic acid (AA) metabolites formed via cytochrome P¬450 (CYP-450). VSMC proliferation was measured by [3H]thymidine incorporation in cultured cells treated by ET-1 (10 to l00 nmol/L) in presence of different inhibitors of CYP-450 (17-ODYA 5 μmol/L), lipoxygenase (LO) (baicalein 20 μmol/L) and cyclooxygenase (COX) (indomethacin 5 μmol/L). ET-1 (10 to 100 nmol/L) induced VSMC proliferation and this effect was attenuated by CYP-450 inhibitor (17-ODYA) and lipoxygenase (LO) inhibitor (baicalein) but not by cyclooxygenase (COX) inhibitor (indomethacin). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) and 12-HETE increased [3H]thymidine incorporation in VSMC. Inhibitors of MAP kinase (PD-98059 50 μmol/L) and cPLA2 (MAFP 50 μmol/L) attenuated ET-1 as well as 20-HETE induced VSMC proliferation. These results suggest AA metabolites via CYP-450 mediates ET-1 induce VSMC proliferation.
Ljuca
Farid
F
Department of Physiology, Faculty of Medicine, University of Tuzla, Univerzitetska 1, 75000 Tuzla, Bosnia and Herzegovina.
Drevensek
Gorazd
G
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism / Q000502:physiology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D051381:Rats; D054507:Receptors, Phospholipase A2 / Q000037:antagonists & inhibitors; D013936:Thymidine / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D044950:Flavanones; D006893:Hydroxyeicosatetraenoic Acids; D054507:Receptors, Phospholipase A2; D016718:Arachidonic Acid; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D020928:Mitogen-Activated Protein Kinases; D013936:Thymidine; D007213:Indomethacin