| Project/Area Number |
14571107
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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 |
Metabolomics
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| Research Institution | Osaka City University |
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Principal Investigator |
SHIOI Atsushi Osaka City University, Graduate School of Medicine, Lecturer, 大学院・医学研究科, 講師 (90260801)
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| Co-Investigator(Kenkyū-buntansha) |
JONO Shuichi Osaka City University, Graduate School of Medicine, Research Associate, 大学院・医学研究科, 助手 (60336790)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | apoE knock-out mouse / atherosclerosis / vascular calcification / osteoprotegerin / coronary artery disease / cartilaginous metaplasia |
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| Research Abstract |
In vitro studies using human vascular smooth muscle cells (HVSMCs) demonstrated that expression of osteoprotegerin (OPG) was down-regulated in HVSMCs by the treatment with inflammatory mediators which acquire calcifying phenotype of HVSMCs. In order to clarify the roles of OPG in the development of atherosclerotic calcification in vivo, we generated apoE/OPG double null mutant (apoE(-/-)OPG(-/-)) mice. Inactivation of OPG gene in apoE-deficient (apoE(-/-)OPG(+/+)) mice significantly suppressed calcification of atherosclerotic plaques without affecting formation of atherosclerotic lesions. Serum levels of alkaline phosphatase (ALP) were significantly increased in apoE(-/-)OPG(-/-) mice compared with apoE(-/-)OPG(+/+) mice, suggesting that inactivation of OPG gene increases bone turnover, especially bone resorption. There were no significant differences in other serum biochemical parameters between apoE(-/-)OPG(-/-) and apoE(-/-)OPG(+/+) mice. Furthermore, expression of cartilage-specific genes such as type II collagen, Indian hedgehog, and type X collagen was increased in vascular smooth muscle cells derived from the aortas of apoE(-/-)OPG(-/-) mice compared with those of apoE(-/-)OPG(+/+) mice. These data indicate that OPG may contribute to the development of atherosclerotic calcification through modulating chondrogenic differentiation of vascular cells. Finally, clinical studies using patients with coronary artery disease (CAD) demonstrated that serum OPG levels were associated with both the severity of CAD and the degree of coronary artery calcification. Therefore, this project revealed that OPG plays an important role in the development and progression of atherosclerotic calcification.
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