| Co-Investigator(Kenkyū-buntansha) |
SHIMONISHI Manabu National Cardiovascular Center Research Institute Department of Pharmacology, Re, 薬理部, 室員 (70300978)
HATAE Toshihisa National Cardiovascular Center Research Institute Department of Pharmacology, Re, 薬理部, 室員 (10251026)
INOUE Hiroyasu National Cardiovascular Center Research Institute Department of Pharmacology, Se, 薬理部, 室長 (40183743)
YOKOYAMA Chieko National Cardiovascular Center Research Institute Department of Pharmacology, Se, 薬理部, 室長 (90200914)
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| Research Abstract |
The present study have been carried out with vascular endothelial cells, smooth muscle cells and macrophages or with gene-targgetting mice to investigate the mechanism of gene expression of the enzymes involved in the biosynthesis of prostacyclin (PGI_2) and thromboxane, which are cyclooxygenase (COX) synthesizing prostglandin H_2 (PGH_2), and PGI_2 and TX synthases isomerizing PGH_2 to PGI_2 and TX, respectively. The results obtained under this study are as follows. (1) the expression of COX-2, a key enzyme for the synthesis for inflammatory PGs is inhibited by anti-inflammatcry steroid, glucocorticoid. We studied the suppression mechanism of COX--2 gene in endothelial cells by glucocortocoid and charcterizethe role of its receptor. A polyphenol compond, resveratrol was found to inhibit the expression and enzyme activity of COX-2. (2) The gene expression of COX-1 and -2, and PGI_2 synthase in blood vessels was examined by in situ hybridization with anti-seuse RNAs. The expression levels of these enzymes in aorta were higher than those in vein. Especially, the level of COX-2 in vein was quite low. (3) High level of expression of PGI_2 synthase was gained with a baculovirus system. The overexpression of PGI_2 synthase in kidney 293 cells was found to induce apoptosis. (4) The expression of PGI_2 synthase in rat peritoneal macrphages was decreasedby activation using casein or BCG with concomitant increase of TX synthase level. (5) PGI_2 synthase-deficieint mice exhibited a morphological change in kidney, and pathological analysis of the mice showed the thickning of arteries, atherosclerosis or fibrosis.
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