Cyclooxygenase-2 induction by lysophosphatidylcholine in cultured rat vascular smooth muscle cells: involvement of the p38MAPK pathway.
Lysophosphatidylcholine (lysoPC) stimulates the release of prostaglandins (PGs) in various cells and tissues. Cyclooxygenase (COX)-2 has recently emerged as a key regulator of PG synthesis. We investigated whether lysoPC regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). LysoPC strongly increased the expression of COX-2 mRNA in a time- and dose-dependent manner. COX-2 protein expression also was increased by lysoPC. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 significantly suppressed lysoPC-induced COX-2 mRNA and protein expression, but not a p42/44MAPK kinase (MEK-1) inhibitor, PD98059. LysoPC did not increased the transcription of the COX-2 gene, as assayed with a COX-2 promoter/luciferase chimeric plasmid and suppressed the decay of COX-2 mRNA. SB203580 markedly enhanced the decay of COX-2 mRNA induced by lysoPC, implying that p38MAPK activated by lysoPC helps to regulate COX-2 by stabilizing its mRNA. The COX-2 specific inhibitor NS-398 attenuated lysoPC-stimulated DNA and protein synthesis as well as PGE(2) production by VSMCs. These results suggest that in rat VSMCs lysoPC regulates COX-2 expression and PG production and also modulates cell proliferation through p38MAPK-mediated signaling pathways.
Yamakawa
Tadashi
T
Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohoma, Japan. Yamakat@urahp.yokohama-cu.ac.jp
Ohnaka
Keizo
K
Tanaka
Shun-Ichi
S
Utsunomiya
Hirotoshi
H
Kamei
Junzo
J
Kadonosono
Kazuaki
K
D000818:Animals; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000187:drug effects* / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009578:Nitrobenzenes / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D052246:Cyclooxygenase 2 Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D008244:Lysophosphatidylcholines; D009578:Nitrobenzenes; D011725:Pyridines; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one