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Epicardial Adipose Tissue as a Source of Nuclear Factor-B and c-Jun N-Terminal Kinase Mediated Inflammation in Patients with Coronary Artery Disease

Unit for Diabetes and Metabolism (A.R.B., A.L.H., D.C.P., N.F.d.S., E.M.Y., S.K., P.G.M.), University of Warwick, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Coventry CV2 2DX, United Kingdom; Department of Cardiothoracic Surgery (N.H., A.M.R., R.S.B., D.P.), University of Birmingham, Birmingham B15 2TH, United Kingdom; Department of Health Sciences (K.K.), University of Leicester, Leicester General Hospital, and Department of Cardiovascular Sciences (M.J.D.), University of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom

Address all correspondence and requests for reprints to: Dr. P. G. McTernan, Unit for Diabetes and Metabolism, University of Warwick, Warwick Medical School, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom. E-mail: p.g.mcternan{at}warwick.ac.uk.

Context: Visceral adipose tissue (AT) is known to confer a significantly higher risk of type 2 diabetes and cardiovascular disease. Epicardial AT has been shown to be related to cardiovascular disease and myocardial function through unidentified mechanisms. Epicardial AT expresses an inflammatory profile of proteins; however, the mechanisms responsible are yet to be elucidated.

Objectives: The objectives of the study were to: 1) examine key mediators of the nuclear factor-B (NFB) and c-Jun N-terminal kinase (JNK) pathways in paired epicardial and gluteofemoral (thigh) AT from coronary artery disease (CAD) and control patients and 2) investigate circulating endotoxin levels in CAD and control subjects.

Design: Serums and AT biopsies (epicardial and thigh) were obtained from CAD (n = 16) and non-CAD (n = 18) patients. Inflammation was assessed in tissue and serum samples through Western blot, real-time PCR, ELISAs, and activity studies.

Results: Western blotting showed epicardial AT had significantly higher NFB, inhibitory-B kinase (IKK)-, IKKβ, and JNK-1 and -2 compared with thigh AT. Epicardial mRNA data showed strong correlations between CD-68 and toll-like receptor-2, toll-like receptor-4, and TNF-. Circulating endotoxin was elevated in patients with CAD compared with matched controls [CAD: 6.80 ± 0.28 endotoxin unit(EU)/ml vs. controls: 5.52 ± 0.57 EU/ml; P<0.05].

Conclusion: Epicardial AT from patients with CAD shows increased NFB, IKKβ, and JNK expression compared with both CAD thigh AT and non-CAD epicardial AT, suggesting a depot-specific as well as a disease-linked response to inflammation. These studies implicate both NFB and JNK pathways in the inflammatory profile of epicardial AT and highlight the role of the macrophage in the inflammation within this tissue.

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