Published online before print March 22, 2007, doi: 10.1161/01.RES.0000264498.60702.0d
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© 2007 American Heart Association, Inc.
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5-Lipoxygenase–Activating Protein
A Potential Link Between Innate and Adaptive Immunity in Atherosclerosis and Adipose Tissue Inflammation
From the Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Correspondence to Magnus Bäck, MD, PhD, Center for Molecular Medicine, Karolinska University Hospital, L8:03, 171 76 Stockholm, Sweden. E-mail Magnus.Back{at}cmm.ki.se
Transforming growth factor-ß (TGF-ß) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE–/– mice with a dominant-negative TGFß type II receptor (dnTGFßRII) 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 dnTGFßRII 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 B4 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.
Key Words: atherosclerosis • cytokines • inflammation • leukotriene • lipid metabolites • lipoxygenase • metabolism
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