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      The Role of High Mobility Group Box 1 Protein in Interleukin-18-Induced Myofibroblastic Transition of Valvular Interstitial Cells

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          Abstract

          Background: Increased levels of interleukin-18 (IL-18) and high mobility group box 1 protein (HMGB1) have been reported in patients with calcific aortic valve disease (CAVD). However, the role of IL-18 and HMGB1 in the modulation of the valvular interstitial cell (VIC) phenotype remains unclear. We hypothesized that HMGB1 mediates IL-18-induced myofibroblastic transition of VICs. Methods: The expression of IL-18, HMGB1 and α-smooth muscle actin (α-SMA) in human aortic valves was evaluated by immunohistochemical staining, real-time polymerase chain reaction and immunoblotting. Plasma concentrations of IL-18 and HMGB1 were measured using the ELISA kit. Cultured human aortic VICs were used as an in vitro model. Results: Immunohistochemistry and immunoblotting revealed increased levels of IL-18, HMGB1 and α-SMA in calcific valves. Circulating IL-18 and HMGB1 levels were also higher in CAVD patients. In vitro, IL-18 induced upregulation of HMGB1 and α-SMA in VICs. Moreover, IL-18 induced secretion of HMGB1 to the extracellular space and activation of nuclear factor kappa-B (NF-κB). Blockade of NF-κB abrogated the upregulation and release of HMGB1 induced by IL-18. Whereas HMGB1 inhibition attenuated the IL-18-induced expression of α-SMA, HMGB1 enhanced the effect of IL-18. Conclusions: We demonstrated for the first time that both tissue and plasma levels of IL-18 and HMGB1 were increased in patients with CAVD. Mechanically, HMGB1 mediated IL-18-induced VIC myofibroblastic transition.

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          Novel role of PKR in inflammasome activation and HMGB1 release

          The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1) 1-5 . During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
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            The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology.

            The study of the cellular and molecular pathogenesis of heart valve disease is an emerging area of research made possible by the availability of cultures of valve interstitial cells (VICs) and valve endothelial cells (VECs) and by the design and use of in vitro and in vivo experimental systems that model elements of valve biological and pathobiological activity. VICs are the most common cells in the valve and are distinct from other mesenchymal cell types in other organs. We present a conceptual approach to the investigation of VICs by focusing on VIC phenotype-function relationships. Our review suggests that there are five identifiable phenotypes of VICs that define the current understanding of their cellular and molecular functions. These include embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), progenitor VICs (pVICs), and osteoblastic VICs (obVICs). Although these may exhibit plasticity and may convert from one form to another, compartmentalizing VIC function into distinct phenotypes is useful in bringing clarity to our understanding of VIC pathobiology. We present a conceptual model that is useful in the design and interpretation of studies on the function of an important phenotype in disease, the activated VIC. We hope this review will inspire members of the investigative pathology community to consider valve pathobiology as an exciting new frontier exploring pathogenesis and discovering new therapeutic targets in cardiovascular diseases.
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              HMGB1 in vascular diseases: Its role in vascular inflammation and atherosclerosis.

              The nuclear protein high mobility group box 1 (HMGB1) has been suggested to be involved in the pathogenesis of several vascular diseases such as systemic vasculitis and atherosclerosis. In systemic vasculitides including ANCA-associated vasculitis and Kawasaki disease, serum HMGB1 levels are higher in patients with active disease compared to healthy controls. In atherosclerotic disease, HMGB1 displays increased expression in nuclei and cytoplasm of macrophages and smooth muscle cells in the atherosclerotic lesions, and is implicated in the progression of the atherosclerotic plaque. Experimental models of acute coronary syndromes and cerebrovascular accidents show that HMGB1 is not only involved in the amplification of the inflammatory response during acute ischemic injury, but also in the recovery and remodeling process after ischemia. Patients with acute coronary syndromes or stroke present significantly higher serum levels of HMGB1 than healthy controls and levels are associated with disease severity and mortality. Here we review clinical and experimental studies dealing with the role of HMGB1 in vascular diseases. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2016
                October 2016
                09 July 2016
                : 135
                : 3
                : 168-178
                Affiliations
                aDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, and bDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, cDepartment of Cardiothoracic Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, and dDepartment of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
                Author notes
                *Nianguo Dong or Fei Li, Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022 (China), E-Mail dongnianguo@hotmail.com or lifei_union@sina.com
                Article
                447483 Cardiology 2016;135:168-178
                10.1159/000447483
                27395056
                693b37bf-7e3c-466e-b702-14a3c1ee5f70
                © 2016 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 25 February 2016
                : 07 June 2016
                Page count
                Figures: 6, Tables: 1, References: 27, Pages: 11
                Categories
                Original Research

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Interleukin-18,Myofibroblasts,Calcific aortic valve disease,High mobility group box 1 protein,Valvular interstitial cells

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