title: 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-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.
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Torres
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.
authors.forename: Changhan
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA mzou@gsu.edu zxie@gsu.edu.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D013481:Superoxides; D008687:Metformin; C486391:Dnm1l protein, mouse; D034281:Dynamins; D005947:Glucose