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Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission
Open accessAbstract
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-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− 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.
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“In diabetes, mitochondrial dysfunction induces and aggravates macrovascular complications [218,219].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [218]
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“Wang et al., reported that treatment of streptozotocin (STZ)-induced diabetic mice with metformin (300 mg/kg/day) in their drinking water for 4 weeks suppressed mitochondrial fission through inhibition of dynamin-related protein (Drp1) via an AMPK-dependent process and enhanced mitochondrial fusion (186).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [186]
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Metadata
- Authors
- Wang, Q., Zhang, M., Torres, G., Wu, S., Ouyang, C., Xie, Z., & Zou, M.-H.
- Affiliations
- Georgia State University (US)
- University of Oklahoma Health Sciences Center (US)
- Corresponding author
- Xie, Zhonglin
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-10-13
- Volume
- 66
- Issue
- 1
- Pages
- 193-205
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5204316
- OpenAlex
- W2531934030
- Cited by
- 370
- References
- 55
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 30 · 2023: 38 · 2022: 53 · 2021: 56 · 2020: 43 · 2019: 40 · 2018: 35 · 2017: 18 · 2016: 1
- FWCI
- 16.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung and Blood Institute (HL-128014, HL-132500, HL-079584, HL-080499, HL-089920, HL-110488)
- National Institute on Aging (AG-047776)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- metformin, mitochondrial fission, Drp1, AMPK, endothelial cells, mitochondrial superoxide, oxidative stress, endothelial dysfunction, vascular inflammation, ApoE-deficient mice, streptozotocin-induced diabetes, macrovascular complications
- MeSH terms
- Animals, Apolipoproteins E, Diabetes Mellitus, Experimental, Glucose, Humans, Male, Metformin, Superoxides, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Dynamins, Atherosclerosis, Mice, Human Umbilical Vein Endothelial Cells, Mitochondrial Dynamics
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