title: Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation.
abstract: BACKGROUND
  The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain.
  
  
  OBJECTIVE
  We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation.
  
  
  RESULTS
  Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1.
  
  
  CONCLUSIONS
  We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis.
authors.affiliation: British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Cuhlmann
authors.forename: Kim
authors.initials: K
authors.lastname: Van der Heiden
authors.forename: David
authors.initials: D
authors.lastname: Saliba
authors.forename: Jordi L
authors.initials: JL
authors.lastname: Tremoleda
authors.forename: Magdy
authors.initials: M
authors.lastname: Khalil
authors.forename: Mustafa
authors.initials: M
authors.lastname: Zakkar
authors.forename: Hera
authors.initials: H
authors.lastname: Chaudhury
authors.forename: Le Anh
authors.initials: le A
authors.lastname: Luong
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Irina
authors.initials: I
authors.lastname: Udalova
authors.forename: William
authors.initials: W
authors.lastname: Gsell
authors.forename: Hazel
authors.initials: H
authors.lastname: Jones
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Rob
authors.initials: R
authors.lastname: Krams
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D012039:Regional Blood Flow / Q000235:genetics / Q000502:physiology*; D033081:Shear Strength / Q000502:physiology; D051996:Transcription Factor RelA / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D051996:Transcription Factor RelA; D048055:Mitogen-Activated Protein Kinase 8