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document
Activator protein-1 ( AP-1 ) signalling in human atherosclerosis : results of a systematic evaluation and intervention study . 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 μg/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 .
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Intervention_Pharmacological
Activator protein-1 ( AP-1 )
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Intervention_Pharmacological
AP-1 ( activator protein-1 )
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Intervention_Pharmacological
AP-1 activation
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Intervention_Pharmacological
AP-1 inhibition
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Intervention_Pharmacological
AP-1 activation
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Intervention_Pharmacological
AP-1 inhibition
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Outcome_Physical
AP-1 inhibition
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Participant_Condition
atherosclerosis
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Participant_Condition
atherosclerotic disease
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Participant_Condition
atherosclerosis
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Participant_Condition
aortic wall