title: 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation.
abstract: Transforming growth factor-beta (TGF-beta) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE(-/-) mice with a dominant-negative TGFbeta type II receptor (dnTGFbetaRII) on CD4(+) and CD8(+) T cells display aggravated atherosclerosis. The aim of the present study was to elucidate the mechanisms involved in this enhanced inflammatory response. Gene array analyses identified the 5-lipoxygenase-activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFbetaRII transgenic ApoE(-/-) mice compared with their ApoE(-/-) littermates, a finding that was confirmed by real-time quantitative RT-PCR. Aortas from the former mice in addition produced increased amounts of the lipoxygenase product leukotriene B(4) after ex vivo stimulation. FLAP protein expression in both the aorta and adipose tissue was detected in macrophages, but not in T cells. Four weeks of treatment with the FLAP inhibitor MK-886 (10 mg/kg in 1% tylose delivered by osmotic pumps) significantly reduced atherosclerotic lesion size and T-cell content. Finally, FLAP mRNA levels were upregulated approximately 8-fold in adipose tissue derived from obese ob/ob mice. In conclusion, the results of the present study suggest a key role for mediators of the 5-lipoxygenase pathway in inflammatory reactions of atherosclerosis and metabolic disease.
authors: Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. Magnus.Back@cmm.ki.se
authors: Magnus
authors: M
authors: Bäck
authors: Ariane
authors: A
authors: Sultan
authors: Olga
authors: O
authors: Ovchinnikova
authors: Göran K
authors: GK
authors: Hansson
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007109:Immunity; D007113:Immunity, Innate; D007211:Indoles / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D015854:Up-Regulation; D002722:Chlorobenzenes
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins; D007211:Indoles; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; C548593:Alox5ap protein, mouse; C060893:MK-886; D002722:Chlorobenzenes