Upregulation of endothelin-1 production by lysophosphatidic acid in rat aortic endothelial cells.
Addition of lysophosphatidic acid (LPA) to rat aorta-derived endothelial cells significantly induced preproendothelin-1 (preproET-1) mRNA expression. PreproET-1 mRNA levels reached a plateau within 1 h after the addition of 0.5 microM LPA and declined after 2 h. The induction was superinduced by cycloheximide and was blocked by actinomycin D. Suramin, an LPA receptor antagonist, abolished the induction of preproET-1 mRNA by LPA. Protein kinase C inhibitors, H7 and bisindolylmaleimide, were able to block the induction. Transient transfection experiment revealed that the elevated preproET-1 mRNA was a result of the activation of ET-1 gene activity. Electrophoretic mobility shift assay revealed that LPA stimulated the binding of AP-1. The secreted level of ET-1 was elevated 2.3-fold after 12 h of stimulation with LPA. Our results suggest that the upregulation of preproET-1 by LPA may serve to augment and prolong the vasoconstriction action of LPA.
Division of Geriatric Medicine, James Quillen School of Medicine, East Tennessee State University, Box 70429, and Veterans Affairs Medical Center, Johnson City, TN 37614, USA.
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics*; D016232:Endothelins / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D007211:Indoles; D008246:Lysophospholipids; D008301:Maleimides; D011498:Protein Precursors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; C088060:bisindolylmaleimide