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Xiaoxi Qiao, Jing Han, Xiuli Liu, Tongrong Zhou, Paul A Edwards, Hua Gao; Metformin Inhibits TNFα-induced NFκB Signaling Pathway Activation in Human Retinal Vascular Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4396.
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Metformin is a widely used anti-diabetic drug to treat type II diabetes. Our recent clinical study indicates that metformin may reduce the rate of proliferative diabetic retinopathy. The purpose of this study was to determine if metformin has anti-inflammatory effect on human retinal microvascular endothelial cells (hRVECs) and its molecular mechanisms.
Early passages of primary human RVECs (ACBRI 181) were exposed to tumour necrosis factor-α (TNFα) with or without metformin treatment. The activity of AMP-activated protein kinase (AMPK) was manipulated by AICAR, an AMPK activator, and compound C, an AMPK inhibitor. The production of monocyte chemotactic protein-1 (MCP-1) was determined by ELISA. The expression levels of NFκB p65 and phosphorylated AMPK were assessed by western blot.
TNFα at 2.5 ng/mL induced a marked upregulation of NFκB p65 expression by about 2.5-fold and associated increase of downstream inflammatory chemokine MCP-1 secretion by over 10-fold in hRVECs. Metformin pretreatment was able to block TNFα-induced activation of NFκB-MCP-1 pathway in a dose-dependent manner at a dose range of 5-40 mM. Significant reductions (over 50%) of both NFκB p65 protein level and MCP-1 secretion were noticed at low dose of 5 mM metformin (p < 0.05). AMPK activator AICAR (1 mM) elicited similar inhibitory effects on TNFα-induced increases of NFκB p65 level and MCP-1 production. In addition, metformin treatment induced dose-dependent increase of phosphorylated AMPK level either with or without TNFα challenge in hRVECs. Metformin’s inhibitory effects on NFκB p65 level and MCP-1 secretion were partially reversed by co-treatment with AMPK inhibitor compound C in hRVECs.
Metformin has significant anti-inflammatory effect to block TNFα-induced activation of NFκB-MCP-1 signalling pathway in hRVECs. Such effect is partially AMPK-dependent. These results support the notion that metformin treatment could be beneficial to protect retinal vascular endothelial cells from inflammatory insults present in diabetic retinopathy.
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