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Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London EC2Y 5AS, United Kingdom First edition 2017 Copyright © 2017 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-811637-1 ISSN: 1877-1173 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Zoe Kruze Acquisition Editor: Alex White Editorial Project Manager: Helene Kabes Production Project Manager: James Selvam Cover Designer: Victoria Pearson Typeset by SPi Global, India CONTRIBUTORS Valerie Arpino Centre for Critical Illness Research, Lawson Health Research Institute; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Bethan A. Brown School of Clinical Sciences, University of Bristol, Bristol, United Kingdom Yunfei Chen Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Ning Cui Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Kristine Y. DeLeon-Pennell Mississippi Center for Heart Research, UMMC; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, United States Emanuela Falcinelli Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy Sarah J. George School of Clinical Sciences, University of Bristol, Bristol, United Kingdom Sean E. Gill Centre for Critical Illness Research, Lawson Health Research Institute; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Paolo Gresele Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy Min Hu Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Mira Jung Mississippi Center for Heart Research, UMMC, Jackson, MS, United States Raouf A. Khalil Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Christopher K.S. Lee Centre for Critical Illness Research, Lawson Health Research Institute; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Merry L. Lindsey Mississippi Center for Heart Research, UMMC; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, United States ix x Contributors Marcello G. Masciantonio Centre for Critical Illness Research, Lawson Health Research Institute; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Sanjay Mehta Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada Cesar A. Meschiari Mississippi Center for Heart Research, UMMC, Jackson, MS, United States Stefania Momi Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy William C. Parks Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States Wei Peng Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Simon W. Rabkin University of British Columbia, Vancouver, BC, Canada Joseph D. Raffetto Vascular Surgery Research Laboratories, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States Manuela Sebastiano Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy Kate S. Smigiel Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States Helen Williams School of Clinical Sciences, University of Bristol, Bristol, United Kingdom PREFACE Matrix metalloproteinases (MMPs) are a family of structurally related zinc- containing proteolytic enzymes that degrade various components of the extracellular matrix and connective tissue proteins. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins and membrane- type MMPs, and other MMPs. MMPs are important regulators of tissue remodeling, cell migration, and adhesion molecules. In addition to their proteolytic effects on the extracellular matrix, recent studies suggest novel effects of MMPs on transmembrane and intracellular signaling in many cell types including the vascular endothelium and smooth muscle. MMPs are tightly regulated at the transcription level and can be activated by other MMPs or proteases into their proteolytic active forms that interact with var- ious substrates and signaling pathways. MMP activity is also regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), which provide a balancing mechanism to prevent excessive degradation of the extracellular matrix. MMP/TIMP imbalance could lead to pathological conditions and major cardiovascular, metabolic, and musculoskeletal disorders as well as cancer. Modulation of MMP activity using genetic manipulations of endog- enous TIMPs or synthetic pharmacological inhibitors could control MMP activity and may provide new approaches in the management of MMP- related diseases. This volume of Progress in Molecular Biology and Translational Science pro- vides insights into MMPs and Tissue Remodeling in Health and Disease. Because MMPs play a role in a large number of biological processes and could be involved in numerous pathological conditions, we divided this volume into two parts. Part I focuses on Cardiovascular Remodeling, and Part II covers the role of MMPs in other target tissues and diseases and the potential benefits of MMP inhibitors. Renown scientists and researchers have agreed to share their expertise and advanced knowledge on MMPs. In Part I on the role of MMPs on Cardiovascular Remodeling we will cover several important topics regarding the basic biochemical and biological properties of MMPs; the role of MMPs in myocardial infarction and heart failure; the MMP/TIMP balance and microvascular endothelial function and dysfunction; MMPs in blood platelets and leukocyte activation; the role of MMPs in atherosclerosis, aneurysm, and hepatic ischemia/reperfusion injury; and the role of MMPs in remodeling of lower extremity veins and xi xii Preface chronic venous disease. These important reviews were written by research investigators and clinician–scientists from different parts of the world, thus promoting different viewpoints in the pathogenesis of cardiovascular disease and highlighting different approaches in the diagnosis and management of car- diovascular disorders. Thanks to the good work of the contributing authors, and the careful review of our dedicated Reviewers and Editors, we were able to put together these important topics, and present them to our readers in a clear, concise, and informative fashion. I encourage every researcher, clini- cian, medical, graduate, and undergraduate student with aspiration to work in the cardiovascular field to read this state-of-the-art synopsis on MMPs. I would like to dedicate this volume to the late Dr. P. Michael Conn, the past Series Editor of Progress in Molecular Biology and Translational Science. Dr. Conn gave me the great opportunity to be the Editor of this special and timely volume, and for this I will always be very grateful. I also would like to thank our outstanding Senior Editorial Project Manager Mrs. Helene Kabes and our hardworking Editorial Staff who spared no effort to ensure the highest quality of the articles. I also would like to acknowledge our contrib- uting authors not only for their excellent articles but also for sharing some of the reviewers’ duties, and for being very generous with their time and effort in providing other authors with helpful comments and constructive criticism. I particularly wish to thank our readers for their interest in MMPs and cardiovascular remodeling. I encourage all of you to provide feedback and contact