2001 Fiscal Year Final Research Report Summary
Study on Physiological Functions of Synthetic Enzymes for Prostaglandins by Genetically Engineered Mice
| Project/Area Number |
12480195
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
TANABE Tadashi National Cardiovascular Center Research Institute, Department of Pharmacology, Director, 薬理部, 部長 (60025624)
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| Co-Investigator(Kenkyū-buntansha) |
HATAE Toshihisa National Cardiovascular Center Research Institute, Department of Pharmacology, Research Staff, 薬理部, 室員 (10251026)
YOKOYAMA Chieko National Cardiovascular Center Research Institute, Department of Pharmacology, Section Chief, 薬理部, 室長 (90200914)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Prostacyclin / PRARδ / Pulmonary hypertension / Gene therapy / Prostaglandin |
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| Research Abstract |
Prostaglandins (PGs) are important in maintenance of homeostasis of cardiovascular system. However, their detailed physiological roles are still remained to be investigated. Here physiological role of prostacyclin (PGI) has been studied in vivo with PG1 synthase (PGIS)-deficient mice. As it is possible that the deficiency of PGIS increase the production of other PGs such as thromboxane (TX) and PGE, we also made TX syntase knock-out miceand PGE synthase-trangenic mice. Results obtained are followings.
1. PGIS-deficient (PGID) mice producing little PGI showed severe ischemic renal diseases and thickening of kidney arteries. By gene chip analysis of PGID mice, many inflammation-related genewere expressed in the kidneies.
2. Human PGIS was expressed with the HVJ-liposome method in lungs of monocrotaline-treated rats, a model for pulmonary hypertension. The overexpression of PGIS reduced thikening of lung arteires and increased the suvival rate.
3. Overexpression of human PGIS in HEK293 cells induced apoptosis of the cells. The apoptosis was suppressed by antisense DNA for PPARδ or a dominant negative form of PPARδ, suggesting that apoptosis of cells by PGI is induced via PPARδ and reduced in the presence of cAMP. The apoptosis by PGI is also observed in vascular endothelial cells and smooth muscle cells.
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