title: High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-kappa B and AP-1.
abstract: Human endothelial cells cultured under high glucose (HG) conditions were shown before to upregulate several basement membrane proteins, including fibronectin (FN), thus mimicking effects of diabetes. Using human macrovascular (HUVEC) and microvascular (HMEC) endothelial cell lines, we evaluated in the present study some of the key molecular signaling events involved in HG-induced FN overexpression. This expression was shown to be dependent on endogenous endothelin (ET) receptor-mediated signaling. We also examined the roles played by protein kinase C (PKC) and the transcription factors nuclear factor kappaB (NF-kappaB) and activating protein (AP)-1 with respect to such changes. HG, PKC activators, and ETs (ET-1 and ET-3) that increased FN expression also caused activation of NF-kappaB and AP-1. Inhibitors of both NF-kappaB and AP-1 prevented HG- and ET-induced FN production. ET receptor blockade also prevented these HG- and ET-mediated changes. The results of this study indicate that glucose-induced increased FN production in diabetes may be mediated via ET-dependent NF-kappaB and AP-1 activation.
authors.affiliation: Department of Pathology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Shali
authors.initials: S
authors.lastname: Chen
authors.forename: Suranjana
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Chandan
authors.initials: C
authors.lastname: Chakraborty
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D016328:NF-kappa B; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D005947:Glucose