| Project/Area Number |
14571058
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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 |
Endocrinology
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| Research Institution | Tohoku University |
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Principal Investigator |
SUGAWARA Akira Tohoku University, Hospital, Lecturer, 医学部附属病院, 講師 (90270834)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Kazuhisa Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (40260426)
ITO Sadayoshi Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40271613)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | CBP / PPAR-γ / MAP kinase / co-activator / PPAR / アンジオテンシンII |
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| Research Abstract |
Peroxisome proliferator-activated receptor (PPAR)-γ and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-γ suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the -58/-34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-γ function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-γ and modulates its activity. Since both the (MAP) kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-γ-mediated AT1R gene transcription suppression. We observed that 1)PPAR-γ-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect 2)the PPAR-γ-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3)CBP overexpression partially, but significantly, abrogated PPAR-γ-mediated AT1R gene transcription suppression; and 4)the CBP effect was eliminated when the -58/-34 GC-box related element was disrupted. It is therefore speculated that: 1)PPAR-γ phosphorylation by the MAP kinase pathway may attenuate PPAR-γ-mediated AT1R gene transcription suppression through the inhibition of PPAR-γ activity ; and 2)CBP may enhance the activity of the remaining Sp1 on the -58/-34 GC-box related element, resulting in a reduction in PPAR-γ-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-γ in AT1R gene transcription, probably leading to the progression of atherosclerosis.
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