title: High glucose-treated macrophages augment E-selectin expression in endothelial cells.
abstract: E-selectin expression by endothelial cells (ECs) is crucial for leukocyte recruitment during the inflammatory response. Macrophage accumulation and serum E-selectin elevation are features of type 2 diabetes mellitus. However, the interactions between macrophages and ECs in regulating vascular endothelial function are not clearly understood. We investigated the mechanisms underlying the modulation of EC E-selectin expression by high glucose (HG)-treated macrophages. Macrophage-conditioned media (MCM) were prepared from HG-treated macrophages. EC stimulation with HG-MCM induced increases the expression and secretion of E-selectin. By using specific inhibitors and small interfering RNAs, we demonstrate that the activation of the JNK and p38 MAPK pathways are critical for HG-MCM-induced E-selectin expression. Transcription factor ELISA and chromatin immunoprecipitation assays further showed that HG-MCM increases the NF-κB- and AP-1 DNA-binding activities in ECs. The inhibition of NF-κB and AP-1 activation by specific siRNAs blocks the HG-MCM-induced E-selectin promoter activity and expression. Protein arrays and blocking assays using neutralizing antibodies demonstrated that macrophage inflammatory protein 1α and 1β in HG-MCM are major mediators for the induction of EC E-selectin expression. These data support the hypothesis that E-selectin up-regulation stimulated by macrophages may play an active role in atherogenesis in the HG condition and suggest a new mechanism by which arterial disease is accelerated in diabetes.
authors.affiliation: Division of Nephrology, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Te-Chuan
authors.initials: TC
authors.lastname: Chen
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Chien
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
authors.forename: Wen-Shih
authors.initials: WS
authors.lastname: Huang
authors.forename: Jiunn-Ming
authors.initials: JM
authors.lastname: Sheen
authors.forename: Tseng-Hsi
authors.initials: TH
authors.lastname: Lin
authors.forename: Chia-Kuang
authors.initials: CK
authors.lastname: Yen
authors.forename: Mao-Lin
authors.initials: ML
authors.lastname: Sung
authors.forename: Cheng-Nan
authors.initials: CN
authors.lastname: Chen
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D054405:Chemokine CCL3 / Q000276:immunology / Q000378:metabolism; D054407:Chemokine CCL4 / Q000276:immunology / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000235:genetics* / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; C515429:CCL3 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017077:Culture Media, Conditioned; D019040:E-Selectin; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose