title: c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis.
abstract: OBJECTIVE
  Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites.
  
  
  RESULTS
  We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1(-/-), and MKP-1(-/-) mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1.
  
  
  CONCLUSIONS
  Spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries.
authors.affiliation: BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Hera
authors.initials: H
authors.lastname: Chaudhury
authors.forename: Mustafa
authors.initials: M
authors.lastname: Zakkar
authors.forename: Joseph
authors.initials: J
authors.lastname: Boyle
authors.forename: Simon
authors.initials: S
authors.lastname: Cuhlmann
authors.forename: Kim
authors.initials: K
authors.lastname: van der Heiden
authors.forename: Le Anh
authors.initials: le A
authors.lastname: Luong
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Rob
authors.initials: R
authors.lastname: Krams
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D054638:Dual Specificity Phosphatase 1; D053148:Caspase 3