Metformin ameliorates the progression of atherosclerosis via suppressing macrophage infiltration and inflammatory responses in rabbits

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AimsThe present study aimed to investigate the possible effects of metformin on the progression of atherosclerosis in a rabbit model.Main methodsRabbits were randomly divided into three groups (n = 10): the control (Ctrl) group (fed with a chow diet), and two experimental groups, the AS group and the Met group (both received an atherogenic diet). After 2 weeks of acclimatization, the rabbits in the AS and Met groups were given a placebo and metformin, respectively, daily by gavage for 10 weeks. Plasma lipids and inflammatory cytokines were measured. The aorta was isolated for histological and immunohistochemical analysis. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with metformin, and monocyte adhesion and adhesion molecule expression were measured.Key findingsMetformin reduced plasma inflammatory cytokine levels but did not alter lipid content. Compared with that in the AS group, the atherosclerosis burden in the Met group was significantly decreased. The lesional macrophage content was reduced, but the lesional collagen content was not affected in the metformin-treated rabbits, compared with the corresponding levels in the non-treated controls. Furthermore, the aortic mRNA expression levels of adhesion molecules and inflammatory cytokines in the Met group were also significantly reduced compared with those in the AS group. Metformin treatment reduced monocyte adhesion to endothelial cells (ECs) and adhesion molecule expression, and inhibited rabbit monocyte differentiation into macrophages and the macrophage inflammatory response.SignificanceOur results suggest that metformin impeded the progression of atherosclerosis, possibly by suppressing macrophage infiltration and inflammatory responses.Graphical abstractThe anti-atherosclerotic effects of metformin, which may be related to its ability to reduce the levels of inflammatory factors in the blood and to inhibit the expression of adhesion molecules and inflammatory factors by blocking NF-kB translocation.HighlightsMetformin reduced plasma MCP-1, CRP and TNF-α levels but did not alter the lipid content.Metformin suppressed atherosclerotic plaques and decreased the macrophage content in lesions.Metformin attenuated monocyte adhesion to ECs and adhesion molecules expression in vitro.Metformin attenuated inflammatory cytokine release from macrophages derived from rabbit monocytes.

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