title: Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation.
abstract: Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.
authors.affiliation: Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Kuo-Cheng
authors.initials: KC
authors.lastname: Lan
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chen-Yuan
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Kao
authors.affiliation: Department of Urology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-How
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-Tong
authors.initials: KT
authors.lastname: Huang
authors.affiliation: Departments of Laboratory Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Keh-Sung
authors.initials: KS
authors.lastname: Tsai
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis*; D059865:Endoplasmic Reticulum Stress; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000502:physiology*; D007515:Islets of Langerhans / Q000098:blood supply / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017127:Glycation End Products, Advanced; D016328:NF-kappa B; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone