| Project/Area Number |
18390227
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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 |
Circulatory organs internal medicine
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| Research Institution | Gunma University |
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Principal Investigator |
KURABAYASHI Masahiko Gunma University, Graduate School of Medicine, Department of Medicine and Biological Science, Professor (00215047)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Masashi Gunma University, Graduate School of Medicine, Department of Medicine and Biological Science, Associate Professor (60270857)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,820,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2007: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2006: ¥9,800,000 (Direct Cost: ¥9,800,000)
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| Keywords | Calcification / Smooth muscle cell / Transcription factor / Gene expression / Atheroscelrosis / Diabetes / Signaling / Differentiation / 血管 / 血管平滑筋細胞 / カルシウム / 腎不全 / 低酸素 / BMP2 / 血管平滑筋 / 細胞内情報伝達機構 |
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| Research Abstract |
Vascular calcification is a prominent feature of atherosclerosis that is almost certainly associated with chronic vascular inflammation. However, molecular mechanisms of the vascular calcification remains to be determined. Human aortic smooth muscle cells (HASMCs), human monocytic cell line THP-1 cells, and their cocultures were grown in the absence or presence of Ang II, and their alkaline phosphatase (ALP) activity were measured. While neither HASMCs nor THP-1 cells alone showed measurable change in ALP activity in response to Ang II, their coculture exhibited significantly greater ALP activity by Ang II stimulation. Adenovirus expressing Notch intracellular domain (NICD) markedly augmented ALP activity in HASMCs. RT-PCR analysis of HASMCs showed that either NICD overexpression or stimulation by Jagged-1 induced Msx2 gene expression, a key regulator of osteoblastic differentiation. Luciferase assays showed that transcriptional activity of Msx2 promoter was significantly enhanced by Jagged-1stimulation, whereas it was abrogated by a selective Notch signaling inhibitor DAPT. DNA affinity precipitation assays confirmed the binding of RBP-JK, a major mediator of Notch signaling, to the sequence element within the Msx2 promoter. Thus, these results suggest that Ang II promotes osteoblastic differentiation of HASMCs through an induction of Jagged-1 in adjacent monocytes/macrophages, which in turn activates Notch signaling and its downstream target Msx2 gene transcription in HASMCs.
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