Activation of AMPK reduces hyperglycemia-induced mitochondrial ROS production and promotion of mitochondrial biogenesis.
| Project/Area Number |
16590889
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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 |
Metabolomics
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| Research Institution | Kumamoto University |
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Principal Investigator |
NISHIKAWA Takeshi Kumamoto University, Faculty of Medical and Pharmaceutical sciences, Research Associate, 大学院・医学薬学研究部, 助手 (70336212)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAMURA Nobuhiro Kumamoto University, University Hospital, Lecturer, 医学部附属病院, 講師 (40274716)
SAKAKIDA Michiharu Kumamoto University, Faculty of Medical and Pharmaceutical sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (50170577)
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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: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Diabetes Mellitus / Diabetic complications / Mitochondria / Oxidative stress / AMPK / PGC-1α / MnSOD / Mitochondria biogenesis / 活性酸素 |
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| Research Abstract |
The production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) has been proposed as a key event in the development of diabetic complications. The association between the pathogenesis of diabetes mellitus and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetic complications, this study aimed to investigated the effect of metformin and AICAR on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells (HUVECs). Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated adenosine 5'-monophosphate -activated protein kinase (AMPK) activity and increased the expression of PPAR□co-activator-1□(PGC-1□) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPK□1 (DN-AMPK) diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1□ completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factors (NRF)-1 and mitochondrial DNA transcription factor A (mtTFA), and stimulated the mitochondrial proliferation. DN-AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1□ pathway. Our findings suggested that a blockade of hyperglycemia-induced mtROS production though AMPK activation, PGC-1□ induction, or MnSOD induction could therefore be useful in the design of new pharmacological approaches to prevent diabetes complications.
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Report
(3 results)
Research Products
(22 results)
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[Journal Article] Impact of mitochondrial reactive oxygen species (ROS) and apoptosis signal-regulating kinase 1 (ASK1) on insulin signaling.2006
Author(s)
Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Tsuruzoe K, Matsumura T, Ichijo H, Araki E
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Journal Title
Diabetes 55
Pages: 1197-1204
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression.2005
Author(s)
Igata M, Motoshima H, Tsuruzoe K, Kojima K, Matsumura T, Kondo T, Taguchi T, Nakamaru K, Yano M, Kukidome D, Matsumoto K, Toyonaga T, Asano T, Nishikawa T, Araki E
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Journal Title
Circ Res 97
Pages: 837-844
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway.2005
Author(s)
Senokuchi T, Matsumura T, Sakai M, Yano M, Taguchi T, Matsuo T, Sonoda K, Kukidome D, Imoto K, Nishikawa T, Kim-Mitsuyama S, Takuwa Y, Araki E
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Journal Title
J Biol Chem 280
Pages: 6627-6633
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] 15d-PGJ2 inhibits oxidized LDL-induced macrophage proliferation by inhibition of GM-CSF production via in activation of NF-kappaB.2004
Author(s)
Matsuo T, Matsumura T, Sakai M, Senokuchi T, Yano M, Kiritoshi S, Sonoda K, Kukidome D, Pestell RG, Brownlee M, Nishikawa T, Araki E
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Journal Title
Biochem Biophys Res Commun 314
Pages: 817-823
Description
「研究成果報告書概要(欧文)」より
Related Report
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