title: Inhibition by eicosapentaenoic acid of oxidized-LDL- and lysophosphatidylcholine-induced human coronary artery smooth muscle cell production of endothelin.
abstract: The objectives of the present study were (1) to determine whether oxidized low-density lipoprotein (LDL) and lysophosphatidylcholine (lyso-PC), a major phospholipid component of oxidized LDL, stimulate the production of endothelin-1 (ET)-1 in cultured human coronary artery smooth muscle cells (SMCs), and (2) to examine the possible effect of an antiatherogenic agent, eicosapentaenoic acid (EPA), on oxidized-LDL- and lyso-PC-stimulated ET-1 production in these cells. Oxidized LDL (10-50 microg/ml) and lyso-PC (10(-7) to 10(-5) mol/l) stimulated ET-1 production in a concentration-dependent manner. By contrast, the effects of native LDL and phosphatidylcholine were modest or absent. Lyso-PC (10(-7) to 10(-5) mol/l) and oxidized LDL (10-50 microg/ml) significantly induced particulate protein kinase C (PKC) activation. Lyso-PC- and oxidized-LDL-stimulated ET-1 production was significantly inhibited by PKC inhibitor, PKC (19-36). EPA (80-160 micromol/l) clearly suppressed ET-1 production stimulated by oxidized LDL and lyso-PC in a concentration-dependent manner. Furthermore, EPA (160 micromol/l) significantly inhibited lyso-PC (10(-5) mol/l)- and oxidized LDL (50 microg/ml)-induced particulate PKC activation. Results suggest that oxidized LDL and lyso-PC stimulate ET-1 production by a mechanism involving activation of PKC, and that EPA suppresses ET-1 production stimulated by lyso-PC as well as oxidized LDL probably through the modulation of PKC in human coronary artery SMCs. EPA may exert an antiatherosclerotic effect, in part, through these mechanisms.
authors.affiliation: Second Department of Internal Medicine, Kagawa Medical University School of Medicine, Kagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kohno
authors.forename: K
authors.initials: K
authors.lastname: Ohmori
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
authors.forename: I
authors.initials: I
authors.lastname: Kondo
authors.forename: T
authors.initials: T
authors.lastname: Noma
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Mizushige
authors.forename: A K
authors.initials: AK
authors.lastname: Mandal
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D019332:Endothelin-1 / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010982:Platelet-Derived Growth Factor; C099252:oxidized low density lipoprotein; C072093:protein kinase C (19-36); D000804:Angiotensin II; D015118:Eicosapentaenoic Acid; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate