title: Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study.
abstract: 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.
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: C Arnoud
authors.initials: CA
authors.lastname: Meijer
authors.forename: Pum A A
authors.initials: PA
authors.lastname: Le Haen
authors.forename: Rogier A
authors.initials: RA
authors.lastname: van Dijk
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Hira
authors.forename: Jaap F
authors.initials: JF
authors.lastname: Hamming
authors.forename: J Hajo
authors.initials: JH
authors.lastname: van Bockel
authors.forename: Jan H
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D000368:Aged; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D018450:Disease Progression; D004311:Double-Blind Method; D004318:Doxycycline / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D018808:Transcription Factor AP-1; D002097:C-Reactive Protein; D048031:JNK Mitogen-Activated Protein Kinases; D004318:Doxycycline
references.citation: J Am Acad Dermatol. 2006 Feb;54(2):258-65
references.pmid: 16443056
references.citation: Clin Sci (Lond). 2008 Jun;114(11):687-97
references.pmid: 18078385
references.citation: Invest Ophthalmol Vis Sci. 2005 Mar;46(3):840-8
references.pmid: 15728539
references.citation: Am J Pathol. 2000 Jun;156(6):1875-86
references.pmid: 10854211
references.citation: J Biol Chem. 1991 Dec 5;266(34):23048-52
references.pmid: 1744101
references.citation: Stroke. 2002 Dec;33(12):2858-64
references.pmid: 12468782
references.citation: Am J Clin Dermatol. 2010;11(3):217-22
references.pmid: 20369903
references.citation: Atherosclerosis. 2010 May;210(1):100-6
references.pmid: 20031134
references.citation: Am J Cardiol. 2002 Feb 21;89(4A):32B-38B; discussion 38B-39B
references.pmid: 11879666
references.citation: Int J Mol Med. 2005 Jan;15(1):57-65
references.pmid: 15583828
references.citation: J Vasc Surg. 2003 Aug;38(2):374-9
references.pmid: 12891123
references.citation: J Infect. 2006 Apr;52(4):243-6
references.pmid: 16176834
references.citation: Mol Med. 2011 Sep-Oct;17(9-10):990-9
references.pmid: 21629969
references.citation: N Engl J Med. 2007 Oct 11;357(15):1477-86
references.pmid: 17928595
references.citation: Cardiovasc Res. 2000 Mar;45(4):1026-34
references.pmid: 10728429
references.citation: J Am Coll Cardiol. 1993 Aug;22(2):459-67
references.pmid: 8335815
references.citation: J Clin Endocrinol Metab. 2004 Apr;89(4):1773-8
references.pmid: 15070944
references.citation: Clin Sci (Lond). 2001 Jan;100(1):13-7
references.pmid: 11115412
references.citation: Diabetes Care. 1999 Sep;22(9):1536-42
references.pmid: 10480522
references.citation: Clin Sci (Lond). 2008 Oct;115(7):203-18
references.pmid: 18752467
references.citation: Ann N Y Acad Sci. 2010 Oct;1207:23-31
references.pmid: 20955422
references.citation: Am J Pathol. 2002 Mar;160(3):1089-95
references.pmid: 11891205
references.citation: Am J Cardiol. 2006 Apr 1;97(7):1002-6
references.pmid: 16563905
references.citation: Arterioscler Thromb Vasc Biol. 2000 May;20(5):1262-75
references.pmid: 10807742
references.citation: Clin Ther. 2005 Sep;27(9):1329-42
references.pmid: 16291409
references.citation: Circulation. 2008 Nov 11;118(20):2073-80
references.pmid: 18955669
references.citation: Pharmacol Res. 2011 Feb;63(2):114-20
references.pmid: 21182947
references.citation: Circulation. 2009 Apr 28;119(16):2209-16
references.pmid: 19364980
references.citation: J Atheroscler Thromb. 2010 Dec 26;17(12):1266-74
references.pmid: 20972354
references.citation: Am Heart J. 2003 Jun;145(6):943-51
references.pmid: 12796748
references.citation: Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):483-8
references.pmid: 12615694
references.citation: Int J Obes (Lond). 2007 Nov;31(11):1671-9
references.pmid: 17471294
references.citation: Inflamm Res. 2005 Aug;54(8):338-43
references.pmid: 16158334
references.citation: Curr Opin Periodontol. 1996;3:85-96
references.pmid: 8624573
references.citation: N Engl J Med. 1992 Feb 6;326(6):381-6
references.pmid: 1729621
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1769-75
references.pmid: 12767663
references.citation: Curr Drug Metab. 2007 Dec;8(8):750-7
references.pmid: 18220555
references.citation: Nat Immunol. 2011 Mar;12(3):204-12
references.pmid: 21321594