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      Persistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal Stent

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          Abstract

          Background

          Studies have pointed out a higher mortality after coronary artery bypass surgery (CABG) in patients with stent.

          Objective

          To evaluate inflammatory markers in peripheral blood cells and in coronary artery tissue samples obtained during CABG in patients with stent compared to controls.

          Methods

          The case series consisted of two groups, one with previous stent implantation (n = 41) and one control (n = 26). The expression of the LIGHT, IL-6, ICAM, VCAM, CD40, NFKB, TNF, IFNG genes was analyzed in peripheral blood cells collected preoperatively. The coronary artery was evaluated for: interleukin-6, ICAM, VCAM, CD40, NFKB, TNF-alpha and IFN-gamma by immunohistochemistry. A total of 176 tissue samples were grouped for analysis in: A1- arteries with stent (n = 38); A2- native arteries from patients with stent in another artery (n = 68); and A3- arteries without stent from controls undergoing routinely CABG surgery (n = 70). A significance level of 0.05 was adopted.

          Results

          Patients with stent showed higher TNF (p = 0.03) and lower CD40 gene expression (p = 0.01) in peripheral blood cells than controls without stent. In coronary artery samples, the TNF-alpha protein staining was higher in the group A1, not only in the intima-media layer (5.16 ± 5.05 vs 1.90 ± 2.27; p = 0.02), but also in the adipose tissue (6.69 ± 3.87 vs 2.27 ± 4.00; p < 0.001). Furthermore, group A1 had a higher interleukin-6 protein staining in adipose tissue than group A3 (p = 0.04).

          Conclusion

          We observed a persistently higher systemic TNF expression associated with exacerbated TNF-alpha and interleukin-6 local production in patients with stents. This finding may contribute to a worse clinical outcome.

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          Most cited references27

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          Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy.

          It has recently been appreciated that atherosclerosis is predominantly an inflammatory process. Atherosclerosis begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages. The development of an atheroma continues as T-cells, mast cells, and other inflammatory cells are recruited to the intima. This collection of inflammatory cells promotes smooth muscle cell replication and extracellular matrix elaboration, thereby increasing the lesion size. Various studies have highlighted that interleukin-6 (IL-6) is an upstream inflammatory cytokine that plays a central role in propagating the downstream inflammatory response responsible for atherosclerosis. IL-6 release is stimulated by acute infections, chronic inflammatory conditions, obesity, and physiologic stress. The high level of IL-6 found in such conditions has a myriad of functions, including hepatic synthesis of acute-phase reactants, activation of endothelial cells, increased coagulation, activation of the hypothalamic-pituitary-adrenal axis, and promotion of lymphocyte proliferation and differentiation. Considering the importance of IL-6 in the development of coronary artery disease, targeting its actions could prove to be beneficial. Individuals with a variant in the IL-6 receptor that impairs classic IL-6 signaling were found to have a decreased risk for coronary heart disease. Tocilizumab is a monoclonal antibody that targets the IL-6 receptor and has been show to alleviate symptoms in patients with rheumatoid arthritis, a disease largely driven by the proinflammatory actions of IL-6. Therefore, further studies are needed to determine the role of tocilizumab and other IL-6 receptor blockers in decreasing the inflammatory response key in the development of atherosclerosis.
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            The secretory function of adipocytes in the physiology of white adipose tissue.

            White adipose tissue, previously regarded as a passive lipid storage site, is now viewed as a dynamic tissue. It has the capacity to actively communicate by sending and receiving different types of signals. An overview of these signals, the external modulators that affect adipose tissue and the secreted signaling molecules, the adipokines, is presented. The secretory function is highlighted in relation to energy metabolism, inflammation and the extracellular matrix and placed in the context of adipose tissue biology. We observe that the endocrine function of adipocytes receives much attention, while its paracrine and autocrine functions are underestimated. Also, we provide examples that species specificity should not be neglected. We conclude that adipose tissue primarily is an energy storage organ, well supported by its secretory function. (c) 2008 Wiley-Liss, Inc.
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              How much is too much? Interleukin-6 and its signalling in atherosclerosis.

              The importance of inflammation as a driver of pathology is no longer confined to autoimmune and infectious diseases. In line with convincing experimental data as well as abundant clinical findings the current view of atherosclerosis points to inflammation as a critical regulator of atherosclerotic plaque formation and progression leading to the fatal clinical endpoints myocardial infarction, stroke or sudden cardiac death. The underlying mechanisms have been a matter of intense research during the last decades. In this regard, the interleukin-6 (IL-6) cytokines and their signalling events have been shown to contribute to both, atherosclerotic plaque development and plaque destabilisation via a variety of mechanisms. These involve the release of other pro-inflammatory cytokines, oxidation of lipoproteins by phospholipases, stimulation of acute phase protein secretion, the release of prothrombotic mediators, and the activation of matrix metalloproteinases. Moreover, the formation of reactive oxygen species generated by vascular enzyme systems may play a critical role in the regulation of IL-6 indicating a cross talk between vasoactive substances i.e. angiotensin II or adrenalin and pro-inflammatory cytokines such as IL-6. In this review we will summarise and discuss the underlying molecular and cellular mechanisms how IL-6 as an early and central regulator of inflammation contributes to atherosclerosis and how this knowledge can be integrated into the clinical context.
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                Author and article information

                Journal
                Arq Bras Cardiol
                Arq. Bras. Cardiol
                abc
                Arquivos Brasileiros de Cardiologia
                Sociedade Brasileira de Cardiologia - SBC
                0066-782X
                1678-4170
                August 2018
                August 2018
                : 111
                : 2
                : 134-141
                Affiliations
                [1 ]Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil
                [2 ]Laboratório de Investigação Molecular em Cardiologia, Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil
                [3 ]Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil
                Author notes
                Mailing Address: Pedro Silvio Farsky Rua Alberto Faria, 248. Postal Code 05459-000, Alto de Pinheiros, São Paulo, SP - Brazil. E-mail: pedro.farsky@ 123456gmail.com
                Article
                10.5935/abc.20180119
                6122910
                30020327
                c2d4d5e2-a414-46f4-a344-0c64e7b6bcc2

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivative License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited and the work is not changed in any way.

                History
                : 20 August 2017
                : 23 February 2018
                Categories
                Original Article

                percutaneous coronary intervention,blood cells,inflammation,stents,polymerase chain reaction,immunohistochemistry,tumor necrosis factor-alpha,interleukin-6

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