Impact of methylglyoxal and high glucose co-treatment on human mononuclear cells.
Hyperglycemia and elevation of methylglyoxal (MG) are symptoms of diabetes mellitus (DM). In this report, we show that co-treatment of human mononuclear cells (HMNCs) with MG (5 microM) and high glucose (HG; 15 - 30 mM) induces apoptosis or necrosis. HG/MG co-treatment directly enhanced the reactive oxygen species (ROS) content in HMNCs, leading to decreased intracellular ATP levels, which control cell death via apoptosis or necrosis. Concentrations of 5 microM MG and 15 mM glucose significantly increased cytoplasmic free calcium and nitric oxide (NO) levels, loss of mitochondrial membrane potential (MMP), activation of caspases-9 and -3, and cell death. In contrast, no apoptotic biochemical changes were detected in HMNCs treated with 5 microM MG and 25 mM glucose, which appeared to undergo necrosis. Pretreatment with nitric oxide (NO) scavengers inhibited apoptotic biochemical changes induced by 5 microM MG/15 mM glucose, and increased the gene expression levels of p53 and p21 involved in apoptotic signaling. The results collectively suggest that the treatment dosage of MG and glucose determines the mode of cell death (apoptosis vs. necrosis) of HMNCs, and that both ROS and NO play important roles in MG/HG-induced apoptosis.
Hsieh
Ming-Shu
MS
Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, 32023, Taiwan.
Chan
Wen-Hsiung
WH
Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, 32023, Taiwan.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D011765:Pyruvaldehyde; D000255:Adenosine Triphosphate; D053148:Caspase 3; D053453:Caspase 9; D005947:Glucose; D002118:Calcium