Activation of AMP-activated protein kinase reduces hyperglycemia-Induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells
Activation of AMP-activated protein kinase reduces hyperglycemia-Induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells
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DOI：
10.2337/diabetes.55.1.120
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发表时间：
2006-01-01
期刊：
影响因子：
7.7
通讯作者：
Araki, E
中科院分区：
文献类型：
--
作者：
Kukidome, D;Nishikawa, T;Araki, E
我们先前提出，高血糖诱导的线粒体活性氧物种(MtROS)的产生是糖尿病并发症发生的关键事件。最近报道了糖尿病及其并发症的发病机制与线粒体生物发生之间的关系。由于二甲双胍被报道在预防糖尿病并发症方面可能发挥额外的益处，我们研究了二甲双胍和5-氨基咪唑-4-甲酰胺核糖核苷(AICAR)对培养的人脐静脉内皮细胞mtROS产生和线粒体生物合成的影响。二甲双胍和AICAR可抑制高血糖诱导的细胞内和mtROS的产生，刺激AMP激活的蛋白激酶(AMPK)活性，增加PGC-1α和锰超氧化物歧化酶(MnSOD)mRNAs的表达。AMPKα1的显性负性形式减弱了二甲双胍和AICAR对这些事件的影响，PGC-1α的过表达完全阻断了高血糖诱导的mtROS的产生。此外，二甲双胍和AICAR还可增加核呼吸因子-1和线粒体DNA转录因子A(MtTFA)的mRNA表达，并刺激线粒体增殖。显性负性AMPK也降低了二甲双胍和AICAR对这些观察的影响。这些结果表明，二甲双胍通过诱导MnSOD，并通过激活AMPK-PGC-1α通路促进线粒体生物发生，从而使高血糖诱导的mtROS产生正常化。
We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator-activated response-gamma coactivator-1 alpha (PGC-1 alpha) and manganese superoxide dismutase (MnSOD) mRNAs. ne dominant negative form of AMPK alpha 1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1 alpha completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative-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 alpha pathway.