Metformin attenuates effects of cyclophilin A on macrophages, reduces lipid uptake and secretion of cytokines by repressing decreased AMPK activity

Abstract

Growing evidence implicates cyclophilin A secreted by vascular wall cells and monocytes as a key mediator in atherosclerosis. Cyclophilin A in addition to its proliferative effects, during hyperglycemic conditions, increases lipid uptake in macrophages by increasing scavenger receptors on the cell's surface. It also promotes macrophage migration across endothelial cells and conversion of macrophages into foam cells. Given the known effects of metformin in reducing vascular complications of diabetes, we investigated the effect of metformin on cyclophilin A action in macrophages. Using an model of cultured macrophages isolated from patients with type 2 diabetes with and without coronary artery disease (CAD), we measured the effect of metformin on cyclophilin A expression, lipid accumulation, expression of scavenger receptors, plasma cytokine levels and AMP-activated protein kinase (AMPK) activity in macrophages. In addition, the effects of metformin on migration of monocytes, reactive oxygen species (ROS) formation, lipid uptake in the presence of cyclophilin A inhibitors and comparison with pioglitazone were studied using THP-1 monocytes. Metformin reduced cyclophilin A expression in human monocyte-derived macrophages. Metformin also decreased the effects of cyclophilin A on macrophages such as oxidized low-density lipoprotein (oxLDL) uptake, scavenger receptor expression, ROS formation and secretion of inflammatory cytokines in high-glucose conditions. Metformin reversed cyclophilin A-induced decrease in AMPK-1α activity in macrophages. These effects of metformin were similar to those of cyclophilin A inhibitors. Metformin can thus function as a suppressor of pro-inflammatory effects of cyclophilin A in high-glucose conditions by attenuating its expression and repressing cyclophilin A-induced decrease in AMPK-1α activity in macrophages.

SIRT1/AMPK and Akt/eNOS signaling pathways are involved in endothelial protection of total aralosides of Aralia elata (Miq) Seem against high‐fat diet‐induced atherosclerosis in ApoE−/− mice

“…As shown in Figure a, compared with the ox‐LDL group, the expression of SIRT1 was significantly increased by TASAES pretreatment. Previous study had reported that ox‐LDL could decrease AMPK activity (Ramachandran et al, ). Therefore, we investigated the protective effects of TASAES on ox‐LDL‐induced AMPK phosphorylation.…”

Plaque microstructures during metformin therapy in type 2 diabetic subjects with coronary artery disease: optical coherence tomography analysis

“…Several putative atheroprotective mechanisms of metformin have been reported. Cell and animal studies have demonstrated that metformin favorably modulates secretion of proinflammatory cytokines and AMP-activated kinase (AMPK) implicated in atherogenesis (4)(5)(6). Metformin has also been shown to enhance the functional activities of high-density lipoprotein (HDL) (7,8).…”

<p>Cyclophilin A (CyPA) as a Novel Biomarker for Early Detection of Diabetic Nephropathy in an Animal Model</p>

“…Previous studies demonstrated that CyPA was a good marker for early detection of renal changes in DN. 5,24,[36][37][38][39] The present study describes the rising urinary CyPA in diabetic rats. We tried to find out the possibility of using the urinary CyPA as a new marker for diagnosis of DN as early as possible.…”