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      MMP-12 and Macrophage Activation in Acute Aortic Dissection

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          Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability.

          Matrix metalloproteinases (MMPs) can degrade strength-giving collagens and other structural proteins of the arterial extracellular matrix. Overproduction of MMPs by monocyte/macrophages could therefore promote atherosclerotic plaque rupture and myocardial infarction. Freshly-recruited monocyte macrophages appear to use a prostaglandin (PG)-dependent pathway to coordinately upregulate a broad and potentially highly-destructive spectrum of MMPs. Differentiated macrophages rely on a series of distinct pathways to selectively upregulate groups of MMPs. Moreover, recent evidence suggests that different macrophage phenotypes express characteristically different spectra of MMPs and their inhibitors. New therapies may result from targeting matrix MMP overproduction.
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            Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection.

            Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action. MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to β-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP(-/-) mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte-differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD. These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II.
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              Inflammatory response is associated with aortic dissection.

              Aortic dissection is an age-dependent life-threatening cardiovascular disease with high mortality rates. Recent research has shown that inflammation plays an important role in aortic dissection. Inflammatory cells, such as lymphocytes and macrophages, not only increase the expression of proteases and cell adhesion molecules but also release reactive oxygen species. These cells also contribute to apoptosis of smooth muscle cells in the aortic artery, and finally lead to medial degradation. This process has been considered to be the principal mechanism for aortic dissection. Furthermore, changes in systemic inflammatory biomarkers are associated with acute-phase reactions and complications in aortic dissection. These biomarkers are also used to predict the prognosis of aortic dissection and to distinguish acute aortic dissection from other chest pain diseases. In addition, elevated inflammatory cell activity in aortic wall, identified by positron emission tomography/computed tomography, is associated with serious clinical symptoms and leads to a poor clinical outcome in aortic dissection. Such observations may provide us with new sights into the mechanism of aortic dissection. In this review, we discuss the role of inflammation in the development and progression of aortic dissection. Understanding this inflammatory process may provide us with new strategies for pharmacological treatment of aortic dissection.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2014
                July 2014
                05 June 2014
                : 128
                : 4
                : 314-315
                Affiliations
                aUOC Medicina Interna, bUOC Dipartimento di Medicina Clinica e Molecolare, cUOS Aterosclerosi e Dislipidemia, dUOC Chirurgia Vascolare, Facoltà di Medicina e Psicologia, Sapienza Università di Roma, Azienda Ospedaliera Sant'Andrea, Rome, Italy
                Author notes
                *Flavia Del Porto, MD, Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e Psicologia Sapienza Università di Roma, Azienda Ospedaliera Sant'Andrea, Via di Grottarossa 1035-1039, IT-00189 Rome (Italy), E-Mail flavia.delporto@uniroma1.it
                Article
                361039 Cardiology 2014;128:314-315
                10.1159/000361039
                24902500
                c4cf4c57-f09d-4385-ba3c-92594a360641
                © 2014 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
                : 27 February 2014
                : 27 February 2014
                Page count
                Pages: 2
                Categories
                Letter to the Editor

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                General medicine, Neurology, Cardiovascular Medicine, Internal medicine, Nephrology

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