Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress.
Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress.
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DOI：
10.1371/journal.pone.0119687
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sunagawa K
中科院分区：
文献类型：
--
作者：
Ikeda M;Ide T;Fujino T;Arai S;Saku K;Kakino T;Tyynismaa H;Yamasaki T;Yamada K;Kang D;Suomalainen A;Sunagawa K
线粒体DNA（mtDNA）拷贝数在动物和人类心力衰竭（HF）中减少，但其在心肌细胞中的作用仍有待阐明。因此，我们研究了在容量超负荷（VO）诱导的HF中，由于人线粒体转录因子A（TFAM）或Twinkle解旋酶的过度表达而导致的mtDNA拷贝数增加的心脏保护功能。两种转基因（TG）小鼠，一种过表达TFAM，另一种过表达Twinkle解旋酶，表现出约2倍的心肌线粒体DNA拷贝数增加。这些TG小鼠表现出类似的离心性肥大和改善心脏功能的衰减相比，野生型（WT）小鼠没有任何恶化的线粒体酶活性响应VO，这是伴随着减少基质金属蛋白酶（MMP）活性和活性氧8周后VO。此外，急性VO诱导的MMP-2和MMP-9的上调也被抑制在24小时在两个TG小鼠。在分离的大鼠心肌细胞中，线粒体活性氧（mitoROS）上调MMP-2和MMP-9的表达，和人TFAM（hTFAM）过表达抑制mitoROS和它们的上调。此外，mitoROS在过表达hTFAM或大鼠Twinkle的H9 c2大鼠成心肌细胞中同样受到抑制，这两种细胞都表现出增加的mtDNA拷贝数。此外，与WT小鼠相比，来自两种TG小鼠的mitoROS和线粒体蛋白氧化被抑制。TFAM或Twinkle的过表达会导致线粒体DNA拷贝数增加，并促进与有限线粒体氧化应激相关的心脏保护作用。我们的研究结果表明，增加mtDNA拷贝数可能是一种有用的治疗策略，以靶向HF中的mitoROS。
Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix-metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared to WT mice. The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF.
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影响因子：
10.8
作者：
GARCIA, R;DIEBOLD, S
通讯作者：
DIEBOLD, S
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作者：
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作者：
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