PMID- 22092038
OWN - NLM
STAT- MEDLINE
DCOM- 20120305
LR  - 20211021
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Print)
IS  - 0143-5221 (Linking)
VI  - 122
IP  - 9
DP  - 2012 May
TI  - Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a 
      systematic evaluation and intervention study.
PG  - 421-8
LID - 10.1042/CS20110234 [doi]
AB  - Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway 
      as a promising target in the treatment of atherosclerotic disease. It is, 
      however, unclear whether these observations apply to human atherosclerosis. 
      Therefore we evaluated the profile of AP-1 activation through histological 
      analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. 
      AP-1 activation was quantified by phospho-c-Jun nuclear translocation 
      (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The 
      effect of AP-1 inhibition on vascular parameters was tested through a double 
      blind placebo-controlled cross-over study of 28 days doxycycline or placebo in 
      patients with symptomatic peripheral artery disease. Vascular function was 
      assessed by brachial dilation as well as by plasma samples analysed for hs-CRP 
      (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 
      (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte 
      chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and 
      fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 
      activation in non-diseased arterial wall (i.e. vessel wall without any signs of 
      atherosclerotic disease). A gradual increase of AP-1 activation was found in 
      non-progressive and progressive phases of atherosclerosis respectively (P<0.044). 
      No significant difference was found between progressive and vulnerable lesions. 
      The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and 
      does not significantly differ from the normal aortic wall (P<0.33). Evaluation of 
      the doxycycline intervention only revealed a borderline-significant reduction of 
      circulating hs-CRP levels (-0.51 mug/ml, P=0.05) and did not affect any of the 
      other markers of systemic inflammation and vascular function. Our studies do not 
      characterize AP-1 as a therapeutic target for progressive human atherosclerotic 
      disease.
FAU - Meijer, C Arnoud
AU  - Meijer CA
AD  - Department of Vascular Surgery, Leiden University Medical Center, Leiden, PO Box 
      9600, 2300 RC Leiden, The Netherlands.
FAU - Le Haen, Pum A A
AU  - Le Haen PA
FAU - van Dijk, Rogier A
AU  - van Dijk RA
FAU - Hira, Mitsuhisa
AU  - Hira M
FAU - Hamming, Jaap F
AU  - Hamming JF
FAU - van Bockel, J Hajo
AU  - van Bockel JH
FAU - Lindeman, Jan H
AU  - Lindeman JH
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Biomarkers)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Transcription Factor AP-1)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - N12000U13O (Doxycycline)
SB  - IM
MH  - Aged
MH  - Aorta/drug effects/metabolism
MH  - Atherosclerosis/*drug therapy/*metabolism/physiopathology
MH  - Biomarkers/blood
MH  - C-Reactive Protein/metabolism
MH  - Cross-Over Studies
MH  - Disease Progression
MH  - Double-Blind Method
MH  - Doxycycline/*pharmacology
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Inflammation Mediators/blood
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Male
MH  - Middle Aged
MH  - Peripheral Arterial Disease/drug therapy/metabolism/physiopathology
MH  - Phosphorylation
MH  - Signal Transduction/drug effects
MH  - Transcription Factor AP-1/*antagonists & inhibitors/*metabolism
PMC - PMC3259695
EDAT- 2011/11/19 06:00
MHDA- 2012/03/06 06:00
PMCR- 2012/01/16
CRDT- 2011/11/19 06:00
PHST- 2011/11/19 06:00 [entrez]
PHST- 2011/11/19 06:00 [pubmed]
PHST- 2012/03/06 06:00 [medline]
PHST- 2012/01/16 00:00 [pmc-release]
AID - CS20110234 [pii]
AID - 10.1042/CS20110234 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2012 May;122(9):421-8. doi: 10.1042/CS20110234.