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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\u2212\/\u2212 mice. In high glucose\u2013exposed 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-\u03b12 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE\u2212\/\u2212\/AMPK-\u03b12\u2212\/\u2212 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.<\/jats:p>","DOI":"10.2337\/db16-0915","type":"journal-article","created":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T22:13:35Z","timestamp":1476396815000},"page":"193-205","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":345,"title":["Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission"],"prefix":"10.2337","volume":"66","author":[{"given":"Qilong","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, 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