c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis.
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.
Chaudhury
Hera
H
BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
Zakkar
Mustafa
M
Boyle
Joseph
J
Cuhlmann
Simon
S
van der Heiden
Kim
K
Luong
Le Anh
le A
Davis
Jeremy
J
Platt
Adam
A
Mason
Justin C
JC
Krams
Rob
R
Haskard
Dorian O
DO
Clark
Andrew R
AR
Evans
Paul C
PC
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
D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D054638:Dual Specificity Phosphatase 1; D053148:Caspase 3