| Project/Area Number |
17590725
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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 |
Circulatory organs internal medicine
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| Research Institution | Mie University |
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Principal Investigator |
ITO Masaaki Mie University, Graduate School of Medicine, Department of Cardiology, Professor, 大学院医学系研究科, 教授 (00223181)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Ryuji Mie University, Graduate School of Medicine, Department of Cardiology, Assistant Professor, 大学院医学系研究科, 助手 (60378346)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | CRP / Rho / Rho-kinase / endothelial cell / PAI-1 / glucose / NF-_KB / 血管内皮細胞 |
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| Research Abstract |
Recently it has become evident that C-reactive protein (CRP) has direct proatherothrombotic effects on vascular cells. We examined the direct effects of CRP on cultured bovine endothelial cells (BAEC) and investigated its underlying signaling.
Incubation of BAEC with human recombinant CRP induced a significant increase in PAI-1 expression. Stimulation of BAEC with CRP significantly increased small GTPase RhoA activation. Pretreatment with TAT-C3 (RhoA inhibitor) and Y-27632 (Rho-kinase inhibitor) significantly inhibited CRP-induced PAI-1 expression. NF-_kB activity was markedly enhanced by CRP and pretreatment with Y-27632 inhibited its activation. Parthenolide, SN50 and BAY 11.7082 (NF-_KB inhibitors) significantly blocked CRP-mediated PAI.1 expression. These data suggested that CRP activates Rho/Rho-kinase signaling, which in turn activates NF-_KB activity, resulting in PAI-1 expression in BAEC. These observations provide evidence for the possible involvement of Rho/Rho-kinase signaling in CRP-induced atherothrombogenesis.
The expression of PAI.1 was also increased in BAEC by the stimulation with high concentration of glucose (23 mM). Similar to the stimulation with CRP, stimulation with high glucose significantly increased RhoA activation and pretreatment with Y-27632 significantly blocked high glucose-induced PAI-1 expression. NF-_KB activity was also significantly enhanced by high glucose, and pretreatment with Y-27632 inhibited high glucose-induced PAI-1 expression. NF-_KB inhibitors significantly blocked high glucose-mediated PAI-1 expression. These data suggested that high glucose-induced PAI-1 expression in endothelial cells is mediated by NF-_KB activation through the Rho/Rho-kinase pathway. Inhibition of Rho/Rho-kinase signaling might be a novel target for diabetes and metabolic syndrome.
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