| Project/Area Number |
13672400
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Showa University |
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Principal Investigator |
OHATA Hisayuki Showa Univ., School of Pharmaceutical Sci., Assistant professor, 薬学部, 助教授 (00119166)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Masayuki Showa Univ., School of Pharmaceutical Sci., Research assistant, 薬学部, 助手 (90307067)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | mechanoreception / mechanosensitive channel / intracellular Ca^<2+> ion concentration / lysophosphatidic acid / lens epithelian cells / laser scanning confocal microscopy / in situ |
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| Research Abstract |
The mechanotransduction plays an important role in maintenance of cellular homeostasis. In endothelial cells, it may be essential for local hemodynamic control. Increase in intracellular Ca^<2+> concentration ([Ca^<2+>]_i) is an important signal for mechanoreception, however, the molecular mechanisms remain unclear. We demonstrated that lysophosphatidic acid (LPA, 0.3-10 μM), a bioactive phospholipid, sensitizes response of [Ca^<2+>]_i to mechanical stress in several cell types. Local increases in [Ca^<2+>]_i within the cell subjected to mechanical stress were visualized in cultured bovine lens epithelial and aortic endothelial cells in the presence of LPA. The phenomenon was termed "Ca^<2+> spots". Pharmacological studies revealed that Ca^<2+> spot is an elementary Ca^<2+>-influx event through mechanosensitive channels. The sensitizing effect of LPA was observed in mouse aorta and renal artery in situ. The increase in endothelial [Ca^<2+>]_i caused subsequent [Ca^<2+>]_i transients and contraction in smooth muscle cells in aorta. We then examined the mechanism of LPA-induced endothelium-dependent vascular contraction. Endothelial Ca^<2+> response and vascular contraction were observed with multi photon laser scanning microscopy. The vascular contraction induced by LPA was inhibited by SQ-29548, an antagonist of thromboxane A_2 (TXA2)/prostagrandin H_2 (PGH2) receptor. Moreover, this contraction was partly inhibited by OKY-046 (ozagrel), an inhibitor of TXA2 synthetase. These results suggest that LPA in the presence of fluid flow induced vascular contraction was regulated by endothelium-derived TXA2/PGH2. We hypothesize that LPA acts as a mechanosensitizer in endothelial
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