Dataset Information

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission.

ABSTRACT: Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE-/- mice. In high glucose-exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-?2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE-/-/AMPK-?2-/- mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

SUBMITTER: Wang Q

PROVIDER: S-EPMC5204316 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission.

Wang Qilong Q Zhang Miao M Torres Gloria G Wu Shengnan S Ouyang Changhan C Xie Zhonglin Z Zou Ming-Hui MH

Diabetes 20161013 1

Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endot ...[more]

PMID: 27737949

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Project description:The highly widespread and infiltrative nature of glioblastoma multiforme (GBM) makes complete surgical resection hard, causing high recurrence rate and poor patients' prognosis. However, the mechanism underlying GBM migration and invasion is still unclear. In this study, we investigated the role of a Ras-related protein Rab32 on GBM and uncovered its underlying molecular and subcellular mechanisms that contributed to GBM aggressiveness. The correlation of Rab32 expression with patient prognosis and tumor grade was investigated by public dataset analysis and clinical specimen validation. The effect of Rab32 on migration and invasion of GBM had been evaluated using wound healing assay, cell invasion assay, as well as protein analysis upon Rab32 manipulations. Mitochondrial dynamics of cells upon Rab32 alterations were detected by immunofluorescence staining and western blotting. Both the subcutaneous and intracranial xenograft tumor model were utilized to evaluate the effect of Rab32 on GBM in vivo. The expression level of Rab32 is significantly elevated in the GBM, especially in the most malignant mesenchymal subtype, and is positively correlated with tumor pathological grade and poor prognosis. Knockdown of Rab32 attenuated the capability of GBM's migration and invasion. It also suppressed the expression levels of invasion-related proteins (MMP2 and MMP9) as well as mesenchymal transition markers (N-cadherin, vimentin). Interestingly, Rab32 transported Drp1 to mitochondrial from the cytoplasm and modulated mitochondrial fission in an ERK1/2 signaling-dependent manner. Furthermore, silencing of Rab32 in vivo suppressed tumor malignancy via ERK/Drp1 axis. Rab32 regulates ERK1/2/Drp1-dependent mitochondrial fission and causes mesenchymal transition, promoting migration and invasion of GBM. It serves as a novel therapeutic target for GBM, especially for the most malignant mesenchymal subtype. Schematic of Rab32 promotes GBM aggressiveness via regulation of ERK/Drp1-mediated mitochondrial fission. Rab32 transports Drp1 from the cytoplasm to the mitochondria and recruits ERK1/2 to activate the ser616 site of Drp1, which in turn mediates mitochondrial fission and promotes mesenchymal transition, migration and invasion of GBM.

Dataset Information

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission.

Publications

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission.

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