Abstract
Dipeptidyl peptidase-4 inhibitors are widely used in type 2 diabetes. Endothelium plays a crucial role maintaining vascular integrity and function. Chronic exposure to high glucose drives to endothelial dysfunction generating oxidative stress. Teneligliptin is a novel dipeptidyl peptidase-4 inhibitor with antioxidant properties. This study is aimed to verify a potential protective action of teneligliptin in endothelial cells exposed to high glucose. Human umbilical vein endothelial cells were cultured under normal (5 mmol/L) or high glucose (25 mmol/L) during 21 days, or at high glucose during 14 days followed by 7 days at normal glucose, to reproduce the high-metabolic memory state. During this period, different concentrations of teneligliptin (0.1, 1.0 and 3.0 µmol/L) or sitagliptin (0.5 µmol/L) were added to cells. Ribonucleic acid and protein expression were assessed for antioxidant response, proliferation, apoptosis and endoplasmic reticulum stress markers. Teneligliptin promotes the antioxidant response in human umbilical vein endothelial cells, reducing ROS levels and inducing Nrf2-target genes messenger ribonucleic acid expression. Teneligliptin, but not sitagliptin, reduces the expression of the nicotine amide adenine dinucleotide phosphate oxidase regulatory subunit P22−phox, however, both blunt the high glucose-induced increase of TXNIP. Teneligliptin improves proliferation rates in human umbilical vein endothelial cells exposed to high glucose, regulating the expression of cell-cycle inhibitors markers (P53, P21 and P27), and reducing proapoptotic genes (BAX and CASP3), while promotes BCL2 expression. Teneligliptin ameliorates high glucose-induced endoplasmic reticulum stress reducing the expression of several markers (BIP, PERK, ATF4, CHOP, IRE1a and ATF6). Teneligliptin has antioxidant properties, ameliorates oxidative stress and apoptotic phenotype and it can overcome the metabolic memory effect, induced by chronic exposure to high glucose in human endothelial cells.
Highlights
Abbreviations Apoptosis signalling kinase-1 β-Actin Bovine serum albumin 5-Bromodeoxyuridine Cardiovascular diseases Cyclin-dependent kinase inhibitor-1a/b 2′,7′-Dichlorofluorescein diacetate 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Dipeptidyl peptidase-4
We used as control the DPP-4 inhibitor sitagliptin at the concentration of 0.5 μmol/ L. a,b Total cellular RNA was isolated from HUVECs and messenger RNA (mRNA) encoding for NOX4 and P22−phox genes were assessed by qRT-PCR and expressed relative to GADPH or ACTB. c Protein expression of CASPASE 3 and P21 was assessed by western blot
Densitometric values were normalized to ACTB and represented relative to the control cells (NG), normalized to 1. d HUVECs proliferation was examined by measuring BrdU incorporation. *p o 0.05 and **p o 0.001 vs. NG. #p o 0.05 and ##p o 0.001 vs. HG. $p o 0.05 and $ $p o 0.001 vs. HM
Summary
Abbreviations Apoptosis signalling kinase-1 β-Actin Bovine serum albumin 5-Bromodeoxyuridine Cardiovascular diseases Cyclin-dependent kinase inhibitor-1a/b 2′,7′-Dichlorofluorescein diacetate 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Dipeptidyl peptidase-4. DPP-4 inhibitors Endothelial cells Endothelial dysfunction Endoplasmic reticulum Fetal bovine serum Gastric inhibitory polypeptide Gentamicin/amphotericin Glucagon-like peptide-1 Heme oxygenase-1 High glucose High-metabolic memory Human aortic endothelial cells Human epidermal growth factor Human recombinant fibroblast growth factorbeta Human umbilical vein endothelial cells NAD(P)H dehydrogenase quinone-1 NAD(P)H oxidase Nicotine amide adenine dinucleotide phosphate Non-fat dried milk Normal glucose Nuclear factor (erythroid-derived 2)-like 2 Reactive oxygen species Real-time polymerase chain reaction Thioredoxin Thioredoxin interacting protein Thioredoxin reductase Type 2 diabetes mellitus Unfolded protein response. Glucagon-like peptide 1 (GLP-1) improves endothelial function in diabetes [7,8,9], so therapeutic strategies for patients with T2DM are focused in increasing the incretin response, either by inhibiting dipeptidyl peptidase-4 (DPP4) activity or by using degradation-resistant GLP-1 analogues [7]. Among DPP-4i, it is recent the commercialization of the potent, long-lasting DPP-4i, teneligliptin. It has a unique structure characterized by five consecutive rings, explaining its powerful activity. DPP-4i have shown an antioxidant capacity [12], no studies have evaluated a possible difference between them, as well as if this property can impact on HG-induced damage to ECs
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