Elucidation of the underlining molecular mechanisms of mitochondrial DNA and hear failure
| Project/Area Number |
21790733
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kyushu University |
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Principal Investigator |
IDE Tomomi Kyushu University, 大学病院, 助教 (90380625)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | ミトコンドリア / リモデリング / NFAT / 心不全 / 酸化ストレス / ミトコンドリアDNA |
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| Research Abstract |
In the present study, we aimed to the three points ;
1) To determine whether mitochondrial DNA copy number is an direct factor for the regulation of remodeling after myocardial infarction.
2) To clarify the underling mechanisms how the copy number of mitochondrial DNA regulate intercellular remodeling signal induced by Angiotensin II or endotherine-1.
3) To establish a method to increase mitochondrial DNA.
First of all, it was verified whether the cardiac remodeling is ameliorated by using Twinkle overexpression to determine the role of mitochondria DNA. Overexpression of Twinkle, a mitochondrial DNA helicase, suppressed cardiac remodeling after myocardial infarction as well as Tfam transgenic mice. As a result, the survival rate of mice after infarction was dramatically improved just as observed in Tfam mice. However, the transciption and replication of mitochondria DNA is decreased in Tfam transgenic mice whereas increased in Twinkle transgenic mice. From those data, we speculated the im
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portance and the impact of mitochondria DNA copy number as a protector against cardial remodeling. In order to establish a method to increase mitochondria DNA by exogenously administered Tfam, we prepared recombinant human TFAM protein by GST fusion gene purification protocol. Recombinant TFAM was recruited into mitochondria of cardiac myocytes, and there were no morphological changes in mitochondria observed by electron microscopy.
A treatment with TFAM dose-dependently increased the mtDNA copy number maximum about 2-folds, and inhibited mitochondrial reactive oxygen species generation.
Next, we examined Tfam and increased mitochondria DNA on the intracellular signaling for pathological cardiac hypertrophy and remodeling.
Next we investigated the effects of TFAM on the nuclear factor of activated T cell (NFAT) signaling, which is a major transcriptional factor regulating pathological hypertrophy and remodeling. TFAM inhibited NFAT nuclear translocation induced by angiotensin II (AngII) and endothelin 1 (ET-1) significantly. TFAM also suppressed AngII and ET-1-induced NFAT transcriptional activity and NFAT-dependent gene expression. Finally TFAM inhibited subsequent morphological hypertrophy of cardiac myocytes induced by AngII and ET-1. In addition, intravenously administered recombinant TFAM was recruited into the myocardium in mice, and increased the myocardial mtDNA copy number about 1.8-folds. Conclusion : Recombinant TFAM increases the mtDNA copy number, and attenuates AngII and ET-1-induced hypertrophy of cardiac myocytes via inhibiting NFAT signaling. Recombinant TFAM might be useful as a novel therapeutic strategy for cardiac hypertrophy and failure. Less
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Report
(3 results)
Research Products
(20 results)
