Metformin attenuates expression of endothelial cell adhesion molecules and formation of atherosclerotic plaques via autophagy inductionMetformin attenuates expression of endothelial cell adhesion molecules and formation of atherosclerotic plaques via autophagy induction
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Natural Products and Food - Research and Analysis (NatuRA)
Annals of clinical & experimental metabolism
(2016), p. 1-9
University of Antwerp
The biguanide metformin belongs to the cornerstone therapeutics in treating type II diabetes mellitus. Chronic treatment of diabetic patients with metformin also reduces the development of micro- and macrovascular complications including atherosclerosis. However, the mechanisms driving its anti-atherogenic properties, beyond those of its anti-hyperglycemic effects, are not completely understood. In the present study, we aimed to further clarify the protective effects of metformin against atherosclerosis in a non-diabetic condition. To this end, apolipoprotein E deficient (ApoE-/-) mice were fed a Western-type diet for 20 weeks to induce plaque formation. Meanwhile, animals were treated with metformin (250 mg/kg/day in drinking water) or plain drinking water. Histochemical analysis of plaques in the brachiocephalic artery revealed that metformin inhibited atherosclerotic plaque development (plaque size: 236 ± 30% vs. 176 ± 18%, P < 0.05). Moreover, metformin-treated plaques showed a reduced amount of plaque macrophages (2.1 ± 0.3% vs. 1.3 ± 0.2%, P < 0.05), an increased amount of vascular smooth muscle cells (2.7 ± 0.3% vs. 3.9 ± 0.4%, P < 0.05) and higher collagen content (22 ± 3% vs. 33 ± 4%, P < 0.05). Using GFP-LC3 transgenic mice, we could demonstrate induction of autophagy by metformin in vivo. In vitro experiments with human umbilical vein endothelial cells (HUVECs) indicated that metformin down regulated the cell adhesion molecules ICAM-1 and VCAM-1, and prevented monocyte-to-endothelial cell adhesion. These effects were not evident in metformin-treated HUVECs after silencing of the essential autophagy gene Atg7, suggesting that metformin mediates its effects through induction of autophagy. Overall, we conclude that metformin attenuates atherogenesis and leads to a more stable plaque phenotype in non-diabetic subjects.