Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors could have antiatherosclerotic action, in addition to antihyperglycemic roles. Because macrophage foam cells are key components of atherosclerosis, we investigated the effect of the DPP-4 inhibitor teneligliptin on foam cell formation and its related gene expression levels in macrophages extracted from diabetic db/db (C57BLKS/J Iar -+Leprdb/+Leprdb) mice and type 2 diabetes (T2D) patients ex vivo. We incubated mouse peritoneal macrophages and human monocyte-derived macrophages differentiated by 7-day culture with oxidized low-density lipoprotein in the presence/absence of teneligliptin (10 nmol/L) for 18 hours. We observed remarkable suppression of foam cell formation by teneligliptin treatment ex vivo in macrophages isolated from diabetic db/db mice (32%) and T2D patients (38%); this effect was accompanied by a reduction of CD36 (db/db mice, 43%; T2D patients, 46%) and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression levels (db/db mice, 47%; T2D patients, 45%). Molecular mechanisms underlying this effect are associated with downregulation of CD36 and ACAT-1 by teneligliptin. The suppressive effect of a DPP-4 inhibitor on foam cell formation in T2D is conserved across species and is worth studying to elucidate its potential as an intervention for antiatherogenesis in T2D patients.
Highlights
Type 2 diabetes (T2D) is well known to accelerate the clinical course of atherosclerosis, a condition associated with arterial endothelial dysfunction and several metabolic abnormalities
We previously demonstrated in in vivo studies that glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and a Dipeptidyl peptidase-4 (DPP-4) inhibitor, respectively, prevented the acceleration of atherosclerosis via suppression of foam cell formation regulated by CD36 and ACAT-1 in macrophages isolated from mice [3, 9]
The present study is aimed at elucidating the potential effect of a DPP-4 inhibitor on cardiovascular risk markers, foam cell formation in macrophages, and associated gene expression levels in macrophages isolated from diabetic db/db mice and T2D patients ex vivo
Summary
Type 2 diabetes (T2D) is well known to accelerate the clinical course of atherosclerosis, a condition associated with arterial endothelial dysfunction and several metabolic abnormalities. During the early stage of atherosclerosis, subendothelial accumulation of lipid-laden macrophage-derived foam cells occurs. Accumulation of cholesterol esters in macrophages is a hallmark of foam cell formation, which depends on the uptake of oxidized low-density lipoprotein (ox-LDL) via CD36 [1]. It is decreased by the efflux of free cholesterol mediated by ATP-binding cassette transporter (ABC) A1 and ATP-binding cassette subfamily G member 1 (ABCG1). To protect cells from toxicity resulting from excessive free cholesterol accumulation, the free cholesterol is esterified to cholesteryl ester by acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) [2]. ACAT-1 thereby contributes to foam cell formation by promoting cholesteryl ester accumulation in macrophages
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