| Project/Area Number |
16590657
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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 | Yamagata University |
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Principal Investigator |
KUBOTA Isao Yamagata University, Department of Cardiology, Pulmonology, and Nephrology, Professor, 医学部, 教授 (30161673)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEISHI Yasuchika Yamagata University, Associate Professor, 医学部, 助教授 (40272067)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Toll-like receptor / remodeling / doxorubicin / atherosclerosis / oxidative stress / innate immunity / dxorubicin |
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| Research Abstract |
Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and regulate the innate immunity in response to pathogens. Recent studies have demonstrated that TLRs are activated by endogenous signals such as heat shock proteins and oxidative stress, which may contribute to the pathogenesis of cardiovascular diseases. Oxidative stress is one of the major factors for doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction. Cardiac dysfunction was induced by a single injection of Dox intra-peritoneally in wild type (WT) mice and TLR-2 knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice. NF-kB activation and production of pro-inflammatory cytokines after Dox were suppressed in KO mice compared to WT mice. Numbers of TUNEL positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice. Survival rate was significantly higher in KO mice than in WT mice 14 days after Dox injection.
Next, vascular injury was induced by cuff-placement around the femoral artery in WT and TLR-2 KO mice. After cuff-placement, neo-intimal hyperplasia was markedly suppressed in KO mice compared with WT mice at 2 weeks and 4 weeks after cuff-placement. One week after cuff placement, gene expressions such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1 were significantly decreased in KO mice compared with WT mice. Superoxide production in the cuffed-artery was attenuated in KO mice compared with WT mice.
These findings suggest that Toll-like receptor-2 play a pivotal role in the regulation of cardiovascular remodeling.
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