Dipeptidyl peptidase‑4 inhibitor sitagliptin prevents high glucose‑induced apoptosis via activation of AMP‑activated protein kinase in endothelial cells. 2017

Chao Wu, and Shunying Hu, and Nanping Wang, and Jianwei Tian
Postgraduate Department, Third Military Medical University, Chongqing 400038, P.R. China.

Diabetes mellitus (DM), which is a chronic metabolic disorder, is the primary risk factor of life‑threatening vascular complications. Endothelial apoptosis is important in the development of the initial vascular lesion preceding the diabetic disease. Sitagliptin is a dipeptidyl peptidase‑4 (DPP‑4) inhibitor and extensively used in the clinical treatment of DM. DPP‑4 inhibitors have been demonstrated to be beneficial in the improvement of endothelial homeostasis, however the molecular mechanism by which they exhibit these effects remains to be elucidated. The effect of sitagliptin on endothelial apoptosis was examined in cultured human umbilical vein endothelial cells (HUVECs) incubated with high glucose (HG). The present study demonstrated that treatment of HUVECs with HG increased reactive oxygen species (ROS) production, stimulated mitochondrial depolarization and resulted in cell apoptosis. Pretreatment of HUVECs with sitagliptin significantly prevented HG‑induced endothelial apoptosis. It was further demonstrated that sitagliptin effectively inhibited ROS generation and mitochondrial membrane potential collapse. Similarly, adenosine monophosphate‑activated protein kinase (AMPK) activation by sitagliptin protected against HG‑induced ROS production, mitochondrial membrane potential collapse and endothelial cell apoptosis, as detected via western blotting and flow cytometry analysis. The present study therefore revealed a novel mechanism of sitagliptin‑mediated AMPK activation in preventing endothelial apoptosis and indicated the therapeutic potential of sitagliptin in vascular complications associated with endothelial apoptosis.

UI MeSH Term Description Entries
D007004 Hypoglycemic Agents Substances which lower blood glucose levels. Antidiabetic,Antidiabetic Agent,Antidiabetic Drug,Antidiabetics,Antihyperglycemic,Antihyperglycemic Agent,Hypoglycemic,Hypoglycemic Agent,Hypoglycemic Drug,Antidiabetic Agents,Antidiabetic Drugs,Antihyperglycemic Agents,Antihyperglycemics,Hypoglycemic Drugs,Hypoglycemic Effect,Hypoglycemic Effects,Hypoglycemics,Agent, Antidiabetic,Agent, Antihyperglycemic,Agent, Hypoglycemic,Agents, Antidiabetic,Agents, Antihyperglycemic,Agents, Hypoglycemic,Drug, Antidiabetic,Drug, Hypoglycemic,Drugs, Antidiabetic,Drugs, Hypoglycemic,Effect, Hypoglycemic,Effects, Hypoglycemic
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D005947 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Dextrose,Anhydrous Dextrose,D-Glucose,Glucose Monohydrate,Glucose, (DL)-Isomer,Glucose, (alpha-D)-Isomer,Glucose, (beta-D)-Isomer,D Glucose,Dextrose, Anhydrous,Monohydrate, Glucose
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000068900 Sitagliptin Phosphate A pyrazine-derived DIPEPTIDYL-PEPTIDASE IV INHIBITOR and HYPOGLYCEMIC AGENT that increases the levels of the INCRETIN hormones GLUCAGON-LIKE PEPTIDE-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). It is used in the treatment of TYPE 2 DIABETES. 4-Oxo-4-(3-(trifluoromethyl)-5,6-dihydro(1,2,4)triazolo(4,3-a)pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine,Januvia,MK 0431,MK-0431,MK0431,Sitagliptin,Sitagliptin Monophosphate Monohydrate,Sitagliptin Phosphate Anhydrous,Sitagliptin Phosphate Monohydrate,0431, MK,Anhydrous, Sitagliptin Phosphate,Monohydrate, Sitagliptin Monophosphate,Monohydrate, Sitagliptin Phosphate,Monophosphate Monohydrate, Sitagliptin,Phosphate Anhydrous, Sitagliptin,Phosphate Monohydrate, Sitagliptin,Phosphate, Sitagliptin
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D017382 Reactive Oxygen Species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS. Active Oxygen Species,Oxygen Radical,Oxygen Radicals,Pro-Oxidant,Reactive Oxygen Intermediates,Active Oxygen,Oxygen Species, Reactive,Pro-Oxidants,Oxygen, Active,Pro Oxidant,Pro Oxidants,Radical, Oxygen
D042783 Endothelial Cells Highly specialized EPITHELIAL CELLS that line the HEART; BLOOD VESSELS; and lymph vessels, forming the ENDOTHELIUM. They are polygonal in shape and joined together by TIGHT JUNCTIONS. The tight junctions allow for variable permeability to specific macromolecules that are transported across the endothelial layer. Capillary Endothelial Cells,Lymphatic Endothelial Cells,Vascular Endothelial Cells,Capillary Endothelial Cell,Cell, Capillary Endothelial,Cell, Endothelial,Cell, Lymphatic Endothelial,Cell, Vascular Endothelial,Cells, Capillary Endothelial,Cells, Endothelial,Cells, Lymphatic Endothelial,Cells, Vascular Endothelial,Endothelial Cell,Endothelial Cell, Capillary,Endothelial Cell, Lymphatic,Endothelial Cell, Vascular,Endothelial Cells, Capillary,Endothelial Cells, Lymphatic,Endothelial Cells, Vascular,Lymphatic Endothelial Cell,Vascular Endothelial Cell
D053078 Membrane Potential, Mitochondrial The voltage difference, normally maintained at approximately -180mV, across the INNER MITOCHONDRIAL MEMBRANE, by a net movement of positive charge across the membrane. It is a major component of the PROTON MOTIVE FORCE in MITOCHONDRIA used to drive the synthesis of ATP. Delta Psi M,DeltaPsi M,DeltapsiM,Mitochondrial Membrane Potential,Mitochondrial Transmembrane Potential,M, DeltaPsi,Membrane Potentials, Mitochondrial,Mitochondrial Membrane Potentials,Mitochondrial Transmembrane Potentials,Transmembrane Potential, Mitochondrial,Transmembrane Potentials, Mitochondrial
D054873 Dipeptidyl-Peptidase IV Inhibitors Compounds that suppress the degradation of INCRETINS by blocking the action of DIPEPTIDYL-PEPTIDASE IV. This helps to correct the defective INSULIN and GLUCAGON secretion characteristic of TYPE 2 DIABETES MELLITUS by stimulating insulin secretion and suppressing glucagon release. DPP-4 Inhibitor,DPP-4 Inhibitors,DPP-IV Inhibitor,DPP-IV Inhibitors,DPP4 Inhibitor,DPP4 Inhibitors,Dipeptidyl Peptidase 4 Inhibitor,Dipeptidyl-Peptidase 4 Inhibitor,Dipeptidyl-Peptidase IV Inhibitor,Gliptin,Gliptins,Dipeptidyl-Peptidase 4 Inhibitors,DPP 4 Inhibitor,DPP 4 Inhibitors,DPP IV Inhibitor,DPP IV Inhibitors,Dipeptidyl Peptidase 4 Inhibitors,Dipeptidyl Peptidase IV Inhibitor,Dipeptidyl Peptidase IV Inhibitors,Inhibitor, DPP-4,Inhibitor, DPP-IV,Inhibitor, DPP4,Inhibitor, Dipeptidyl-Peptidase 4,Inhibitor, Dipeptidyl-Peptidase IV

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