| Project/Area Number |
17590768
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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 | Kurume University |
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Principal Investigator |
KAI Hisashi Kurume University, Department of Medicine, Associate Professor, 医学部, 助教授 (60281531)
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| Co-Investigator(Kenkyū-buntansha) |
YASUKAWA Hideo Kurume University, Cardiovascular Research institute, Assistant Professor, 循環器病研究所, 講師 (60289361)
KUDO Hiroshi Kurume University, Department of Medicine, Assistant Professor, 医学部, 助手 (10373135)
TAKAYAMA Narimasa Kurume University, Department of Medicine, Assistant Professor, 医学部, 助手 (70389253)
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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 |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | organ damage / hypertension / heart failure / inflammation / cell, tissue / atherosclerosis |
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| Research Abstract |
The aim of this study was to determine the role of inflammation in organ damages in chronic hypertension model.
(1) Large blood pressure variability-induced aggravation of hypertensive cardiac remodeling
We created a new chronic hypertension model with large blood pressure variability by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHR). Radiotelemetric 24-hour blood pressure monitoring revealed that standard deviation and coefficient of variance of the average of mean blood pressure without changing mean blood pressure in SHR, suggesting that SAD exaggerated blood pressure variability. Seven weeks after SAD or sham operation, the hearts were excised and subjected to the following evaluations. SAD enhanced concentric hypertrophy associated with 1.5-times greater myocyte diameter. Whereas the minimum fibrosis was observed only in the perivascular space in sham+SHR group, SAD+SHR group showed 4-times greater myocardial fibrosis area manifested by ma
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rked perivascular fibrosis and massive, patchy replacement fibrosis. In sham+SHR, only limited number of macrophages were found in the perivascular space. SAD increased the perivascular macrophage infiltration. Real-time RT-PCR analysis demonstrated that SAD induced upregulations of IL-1β, MCP-1, TGF-β, angiotensinogen, angiotensin II type-1 receptor (AT1R) in SHR. When non-depressor dose of candesartan was administered to SAD+SHR, blood pressure variation was not affected. Candesartan prevented the SAD-induced aggravation of myocyte hypertrophy and myocardial fibrosis. The SAD-induced macrophage infiltration and mRNA inductions of MCP-1, TGF-β, angiotensinogen and AT1R were almost abolished in SHR. SAD did not change the circulating levels of catecholamines, angiotensin II and active rennin. Accordingly, it is suggested that large blood pressure variability aggravates hypertensive cardiac remodeling by activating myocardial inflammation. And, the tissue angiotensin system plays a key role in the inflammatory changes induced by large blood pressure variability.
(2) Role of inflammatory changes in vascular remodeling
Interferon-γ is implicated in the trigger of tissue inflammation, including atherosclerosis. We investigated the effect of interferon-γ function blocking on the atherosclerotic plaques in apoE-/-mice by overexpressing the soluble interferon-γ receptor (sIFNgR) in the thigh muscle as means to make the secreted sIFNgR into the circulation to block the binding of interferon-γ to the receptors on the target cells in remote organs. sIFNgR treatment not only regressed but also stabilized the advanced plaque by reducing the lipid and macrophage accumulations and by increasing the fibrotic tissue smooth muscle cell areas. Thus, interferon-γ-mediated inflammation may be a new therapeutic target of atherosclerosis. Less
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