2006 Fiscal Year Final Research Report Summary
Role of Toll-like receptor in cardiovascular remodeling
| Project/Area Number |
17590702
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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 |
TAKEISHI Yasuchika Yamagata University, Department of Cardiology, Pulmonology, and Nephrology, Associate Professor, 医学部, 助教授 (40272067)
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| Co-Investigator(Kenkyū-buntansha) |
GOTO Kaoru Yamagata University, Department of Anatomy and Cell Biology, Professor, 医学部, 教授 (30234975)
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| Project Period (FY) |
2005 – 2006
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| Keywords | hypertrophy / remodeling / heart failure / cell signaling / diacylglycerol kinase / protein kinase C |
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| Research Abstract |
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DAG) and controls cellular DAG levels, thus acting as a negative regulator of protein kinase C (PKC) and subsequent cellular signaling. We previously reported DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. Left ventricular-(LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, Gq protein-coupled receptor signaling pathway including DAG and PKC are involved in this process. We examined whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG) and wild-type (WT) mice. LV chamber dilatation, reduction of L
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V systolic function, and increases in LV weight and lung weight at 4 weeks after MI were attenuated in DGKζ-TG mice compared to WT mice. In the non-infarct area, fibrosis fraction and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were blocked in DGKζ-TG mice. The survival rate at 4 weeks after MI was higher in DGKζ-TG mice than in WT mice.
Thoracic transverse aortic constriction (TAC) was created in DGKζ-TG and WT mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGKζ-TG mice compared to WT mice. Increases in inter-ventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function were observed with echocardiography in WT mice at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGKζ-TG mice. In WT mice, cardiac fibrosis and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were observed at 4 weeks after TAC. However cardiac fibrosis and gene induction of collagen type I and type III, but not transforming growth factor-βl, were blocked in DGKζ-TG mice.
These results demonstrate the first evidence that DGKζ suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKζ also prevents pressure overload-induced cardiac hypertrophy. DGKζ may be a potential novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure. Less
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Research Products
(12 results)
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[Journal Article] Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in heart failure.2007
Author(s)
Arimoto T, Takeishi Y, Niizeki T, Okuyama H, Nozaki N, Hirono O, Watanabe T, Nitobe J, Tsunoda Y, Miyashita T, Takahashi H, Suzuki S, Koyama Y, Kitahara T, Okada A, Takahashi K, Kubota I
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Journal Title
J Card Fail 13
Pages: 34-41
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic2006
Author(s)
Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J
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Journal Title
myocardium. Circulation 113
Pages: 1787-1798
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury2006
Author(s)
Shishido T, Nozaki N, Takahashi H, Arimoto T, Niizeki T, Koyama Y, Abe JI, Takeishi Y, Kubota I
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Journal Title
Biochem Biophys Res Commun 345
Pages: 1446-1453
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hyperuricemia is associated with high cardiac event rates in the elderly person with chronic heart failure.2006
Author(s)
Niizeki T, Takeishi Y, Arimoto T, Okuyama H, Nozaki N, Hirono O, Tsunoda Y, Miyashita T, Takahashi H, Koyama Y, Shishido T, Kubota I
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Journal Title
J Cardiol 47
Pages: 219-228
Description
「研究成果報告書概要(欧文)」より
