| Project/Area Number |
18590238
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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 |
General pharmacology
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| Research Institution | Nara Medical University |
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Principal Investigator |
YOSHIZUMI Masanori Nara Medical University, Pharmacology, Professor (60294667)
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| Co-Investigator(Kenkyū-buntansha) |
SATOH Hiroyasu Nara Medical University, Pharmacology, Lecturer (90150309)
NAKAYAMA Hitoshi Nara Medical University, Pharmacology, Lecturer (50133195)
ISOSAKI Minoru Nara Medical University, Pharmacology, Assistant Professor (60159811)
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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 |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | MAP kinases / Big MAP kinase 1 / Metabolic Syndrome / insulin resistance / Diabetes Mellitus / vascular injury / TNF-α / blood flow / アンジオテンシンII / 炎症 |
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| Research Abstract |
In the current research project, we investigated the physiological significance of big mitogen-activated protein kinase 1 in metabolic syndrome using the model animals of diabetic rats and cultured cells.
1) In the type 2 diabetic rat model OLETF, BMK1 was activated in vascular smooth muscles of small arteries. Similar results were obtained in the atherosclerotic model mice at the site of adventitia of cuff-injured femoral artery. From these findings, it was suggested that BMK1 activation is involved in the pathogenesis of diabetic microangiopathy.
2) In experiments using cultured rat aortic smooth muscle cells (RASMC), platelet-derived growth factor (PDGF) stimulated BMK1 activation in a time and concentration-dependent manner. SHP-2 and Gab1 exist upstream of BMK1 and were activated by PDGF stimulation. PDGF also stimulated RASMC migration, which was inhibited by a transfection with dominant-negative MEK5. These findings suggest that BMK1 is involved in the pathogenesis of inflammatory vascular remodeling.
3) In experiments using human umbilical vein endothelial cells (HUVEC), laminar fluid shear stress stimulated BMK1 activation. TNF-α stimulates c-Jun N-terminal kinase (INK) activation, which was inhibited by laminar flow. Physiological significance of BMK1 in endothelial cells has also confirmed. From these in vivo and in vitro findings, BMK1 is suggested to be involved in vascular injury in metabolic syndrome and BMK1 may be one of the drug targets for treatment of metabolic syndrome.
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