Metformin is a widely used anti-diabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects 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 AMP-activated kinase (AMPK) downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPKα2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE-/-/AMPKα2-/- mice, indicating that metformin exerts an anti-atherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mdivi-1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial function, 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 diabetic patients.
- Received July 26, 2016.
- Accepted October 6, 2016.
- © 2016 by the American Diabetes Association.