Prostacyclin in the cardiovascular system: new aspects and open questions.
Several indications exist that prostacyclin (PGI(2)) release in the cardiovascular system might be affected by cyclooxygenase (COX)-2-specific inhibitors. This could reflect an inhibition of PGI(2) synthesis in the endothelium although in these cells mainly COX-1 is expressed. Inflammation and stress induce COX-2 in smooth muscle cells which could have happened in patients with cardiac diseases. Herein, we show that also cardiomyocytes contain PGI(2) synthase in intercalated discs as a third source of PGI(2) in the cardiovascular system. Another aim of this study was to explain the finding that PGI(2) synthase in lipopolysaccharide (LPS)-treated smooth muscle cells, in contrast to endothelial cells, is resistant to nitration and inhibition by peroxynitrite. By using redox cyclers, the nitration occurred and confirmed our previous hypothesis that a high peroxidative activity of such cells keeps peroxynitrite below the effective levels of 50 nM. Considering enhanced oxidative stress in aged vessels, we postulated and verified that endothelial dysfunction in aged vessels is due to nitration and inhibition of PGI(2) synthase. Such data underline the role of PGI(2) as a potent mediator for regaining and maintaining the normal resting state of cells in a COX-2 dependent fashion.
Klumpp
Georg
G
University of Konstanz, Department of Biology, D-78457 Konstanz, Germany.
Schildknecht
Stefan
S
Nastainczyk
Wolfgang
W
Ullrich
Volker
V
Bachschmid
Markus
M
D000375:Aging; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344
D008070:Lipopolysaccharides; D030421:Peroxynitrous Acid; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase