title: CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction.
abstract: Hyperglycemia-induced endothelial dysfunction is characterized by enhanced inflammatory cytokine and adhesion molecule expression, and endothelial-monocyte adhesion. The adapter molecule CIKS (connection to IKK and SAPK/JNK; also known as Act1 or TRAF3IP2) is an upstream regulator of NF-κB and AP-1, and plays a role in inflammation and injury. Here we show that high glucose (HG; 25mM vs. 5mM d-glucose)-induced endothelial-monocyte adhesion and inhibition of endothelial cell (EC) migration were both reversed by CIKS knockdown. In EC, HG induced CIKS mRNA and protein expression via DPI-inhibitable Nox4-dependent ROS generation. Further, HG induced CIKS transcription and enhanced CIKS promoter-dependent reporter gene activation via Nox4, ROS, AP-1 and C/EBP. Coimmunoprecipitation and immunoblotting revealed CIKS/IKKβ/JNK physical association under basal conditions that was enhanced by HG treatment. Importantly, CIKS knockdown inhibited HG-induced (i) IKKβ and JNK phosphorylation, (ii) p65 and c-Jun nuclear translocation, and (iii) NF-κB- and AP-1-dependent proinflammatory cytokine, chemokine, and adhesion molecule expression. Similar to HG, the deleterious metabolic products of chronic hyperglycemia, AGE-HSA, AOPPs-HSA and oxLDL, also induced CIKS-dependent endothelial dysfunction. Notably, aortas from streptozotocin-induced and the autoimmune type 1 diabetic NOD and Akita mice showed enhanced DPI-inhibitable ROS generation and CIKS expression. Since CIKS mediates high glucose-induced NF-κB and AP-1-dependent inflammatory signaling and endothelial dysfunction, targeting CIKS may delay progression of vascular diseases during diabetes mellitus and atherosclerosis.
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
authors.forename: Balachandar
authors.initials: B
authors.lastname: Venkatesan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Nitin A
authors.initials: NA
authors.lastname: Das
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Carpenter
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Delafontaine
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009000:Monocytes / Q000166:cytology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C556060:6,7-dihydro-5H-pyrrolo(1,2-a)imidazole; D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D011758:Pyrroles; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C515963:Traf3ip2 protein, mouse; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose