Electronic Letters to:

Endocrine Research: A. R. Baker, A. L. Harte, N. Howell, D. C. Pritlove, A. M. Ranasinghe, N. F. da Silva, E. M. Youssef, K. Khunti, M. J. Davies, R. S. Bonser, S. Kumar, D. Pagano, and P. G. McTernan Epicardial Adipose Tissue as a Source of Nuclear Factor-B and c-Jun N-Terminal Kinase Mediated Inflammation in Patients with Coronary Artery Disease J Clin Endocrinol Metab 2009; 94: 261-267 [Abstract] [Full text] [PDF]

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Inflammation in human Epicardial Fat: Who to blame?

Philip G McTernan, David C Pritlove and Alison L Harte.   (23 June 2009)

Inflammation in coronary artery disease: the role of adipose tissue and endotoxemia

Andrea la Sala   (14 May 2009)

Inflammation in human Epicardial Fat: Who to blame? 23 June 2009
Philip G McTernan, Associate Professor Diabetes & Metabolism Univeristy of Warwick, Clinical Science Research Institute, UK, David C Pritlove and Alison L Harte. Send letter to journal: Re: Inflammation in human Epicardial Fat: Who to blame? p.g.mcternan{at}warwick.ac.uk Philip G McTernan, et al.	Dr Andrea la Sala in her consideration of the paper by Baker et al, 2009 examining the potential mechanism for increased inflammation with epicardial adipose tissue (AT) in coronary artery disease (CAD) patients addressed two significant points. First, inflammation with epicardial AT in CAD patients may not arise as a result of macrophage infiltration. Second, the stronger TLRs, TNF-α and CD68 correlation in epicardial and thigh AT from CAD patients does not rule out increased inflammation within non-CAD patients due to noted higher Δ-Cts (1). In addition, that the genes encoding for CD68 in non CAD AT may either be more prone to transcriptional instability and/or CD68 abundance may be an unreliable measure of macrophage infiltration as it may not be cellular specific. To address the first point, it is clear that this paper cannot be viewed in isolation and adds to the current literature suggesting that at least in epicardial fat, macrophage presence/infiltrate heightens the inflammatory response (1-4). Histological images taken of epicardial AT from CAD patients highlight dense inflammatory infiltrates and inflammatory cells noted between individual fat cells (4). Furthermore, subsequent immuohistochemical characterization by Mazurek highlighted cellular infiltrates in epicardial AT such as T cells (CD3+), macrophages (CD68+), and mast cells (tryptase+) (4). However, as Dr Andrea La Sala implies, the interplay between the adipocyte and macrophage appears essential to mediate the inflammatory response, although evidence for this was not detailed in this paper and therefore not specifically addressed. In regards to whether more inflammation arises in epicardial AT from non CAD patients, clearly one must be cautious using only mRNA data. Table 1 from Baker et al, noted that the AT biopsies taken from CAD patients received a much higher percentage of anti-inflammatory agents, including aspirin, specifically known to reduce NF-κB activity. However, in AT from CAD patients the protein expression data consistently remained significantly higher than that of non-CAD protein expression profile in spite of medication given. In addition, previous work using CD45, a marker of macrophages, has shown there to be no expression within isolated human adipocytes for TLRs and therefore by inference the immature pre-adipocytes cell, which would form the majority of the AT tissue, although endothelial cells do express TLRs (5). Further, the Maruzuek paper noted AT depot changes in inflammation which corresponded with macrophage changes denoted by immunohistochemistry. Taken together, this would seem to lessen the direct impact of other cells types to contribute significantly to the inflammatory response (4). Finally, Dr Andrea la Sala considered the importance of endotoxin and whether in patients with long-term endotoxemia there would be endotoxin tolerance. This raises an interesting point. In light of our findings, despite the patients with CAD being given a myriad of drugs which should reduce inflammation, their inflammatory status remained high, along with the endotoxin levels. Our team has noted similar findings in T2DM subjects (3). As such this may still indicate endotoxemia may perpetuate an inflammatory response. References 1. Baker AR, Harte AL, Howell N, Pritlove DC, Ranasinghe AM, da Silva NF, Youssef EM, Khunti K, Davies MJ, Bonser RS, Kumar S, Pagano D, McTernan PG 2009 Epicardial adipose tissue as a source of nuclear factor-κB and c-Jun N-terminal kinase mediated inflammation in patients with coronary artery disease. Clin Endocrinol Metab 94:261-267 2. Kremen J, Dolinkova M, Krajickova J, Blaha J, Anderlova K, Lacinova Z, Haluzikova D, Bosanska L, Vokurka M, Svacina S, Haluzik M. 2006 Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab 91:4620-4627 3. Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S 2007 Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292:E740-E747 4. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, Sarov-Blat L, O'Brien S, Keiper EA, Johnson AG, Martin J, Goldstein BJ, Shi Y 2003 Human Epicardial Adipose Tissue Is a Source. Cardiovasc Diabetol 5:1. 5. McTernan PG, McTernan CL, Chetty R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S. 2002 Increased resistin gene and protein expression in human abdominal adipose tissue. J Clin Endocrinol Metab. 87:2407
Inflammation in coronary artery disease: the role of adipose tissue and endotoxemia 14 May 2009
Andrea la Sala, Head of Laboratory of Molecular and cellular Immunology IRCCS San Raffaele Pisana, Rome, Italy Send letter to journal: Re: Inflammation in coronary artery disease: the role of adipose tissue and endotoxemia andrea.lasala{at}sanraffaele.it Andrea la Sala	Baker et al. in a recent article on the Journal (1) showed increased expression of intracellular molecules mediating inflammatory signaling pathways in epicardial adipose tissue from coronary artery disease patients compared with both coronary artery disease subcutaneous adipose tissue and non-coronary artery disease epicardial adipose tissue. In addition a positive correlation between the expression of mRNA for the macrophage-specific marker CD68 and that for TNF-α, Toll-like receptor (TLR)-2 and -4, was found. The authors concluded that such correlation points out the macrophages as key players in the increased inflammatory activation. However adipose tissue from non-coronary artery disease patients displayed markedly up-regulated mRNA levels for all the genes taken into consideration as indicated by the lower values of ΔCT obtained by real time PCR. This indicated that both epicardial and subcutaneous adipose tissue from non-coronary artery disease subjects contained a higher number of infiltrating macrophages and increased levels of TLR2, TLR4 and TNF-α compared to adipose tissue from coronary artery disease patients. The lack of significant association between CD68 and TNF-α or TLRs in non- coronary artery disease adipose tissue does not indicate a lower degree of inflammation and it can be explained by at least two possibilities. 1) Transcription, stability and translation of mRNA encoding CD68 might be significantly affected by stimuli encountered in the inflamed tissue. Therefore in any given tissue the abundance of CD68 mRNA is far from being a reliable measure of macrophage infiltration. 2) Different cell types other than macrophages might express TLRs and TNF-α in adipose tissue from non-coronary artery disease compared to coronary artery disease subjects due to qualitative differences of the inflammatory infiltrate and/or to differential genes expression by resident cells. Furthermore, Baker et al. suggested that that circulating endotoxin might contribute to sustain systemic inflammation associated with coronary artery disease. As such hypothesis certainly merit considerable attention, one should note that sustained endotoxemia such as that found in coronary artery disease patients might also lead to endotoxin tolerance with blocked production of proinflammatory cytokines rather than systemic inflammation. Reference 1. Baker AR, Harte AL, Howell N, Pritlove DC, Ranasinghe AM, da Silva dF, Youssef EM, Khunti K, Davies MJ, Bonser RS, Kumar S, Pagano D, McTernan PG. 2009. Epicardial Adipose Tissue as a Source of Nuclear Factor-B and c-Jun N-Terminal Kinase Mediated Inflammation in Patients with Coronary Artery Disease. J Clin Endocrinol Metab 94:261-267.