Heparin and acidic fibroblast growth factor interact to decrease prostacyclin synthesis in human endothelial cells by affecting both prostaglandin H synthase and prostacyclin synthase.
Prostaglandin production by cultured human endothelial cells varies with growth conditions. We observed a marked diminution in both spontaneous and inducible production of prostacyclin (PGI2) by human umbilical vein and saphenous vein endothelial cells when they were cultured in the presence of the heparin-binding growth factor, acidic fibroblast growth factor (aFGF) and heparin, compared with PGI2 production during culture in medium lacking these factors. Decreased PGI2 production was related to duration of exposure of the cells to aFGF and heparin and depended on the concentration of both substances. Heparin (1-100 micrograms/ml) strongly potentiated the effects of aFGF but had a limited and variable effect alone. The decrease in PGI2 production correlated with a reduction in the cellular content of immunoreactive prostaglandin H synthase and prostacyclin synthase. Arachidonate deacylation was not decreased. In addition, the eicosanoid profile of endothelial cells was changed by exposure to aFGF and heparin. These studies indicate that heparin acts as a modulator of prostaglandin synthesis in endothelial cells through its interaction with aFGF, mediated by alterations in two key enzymes in the arachidonate metabolic pathway.
Weksler
B B
BB
Department of Medicine, Cornell University Medical College, New York, New York 10021.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; D005346:Fibroblast Growth Factors; D006493:Heparin; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D013917:Thrombin; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone