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Clin Sci (Lond). 2018 Mar 30;132(6):719-738. doi: 10.1042/CS20171523. Print 2018 Mar 30.

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

Author information

1
Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India suryaramachandran@rgcb.res.in cckartha@rgcb.res.in.
2
Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.
3
Achutha Menon Centre for Health Science Studies, Sri Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, India.
4
Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India.
5
Chronic Disease Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.

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 ex vivo 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.

KEYWORDS:

AMPK; Cyclophilin A; Macrovascular complications; atherosclerosis; metformin; oxidative stress

PMID:
29382697
DOI:
10.1042/CS20171523

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