In: ACE Inhibitors ISBN: 978-1-62948-383-2 Editor: Macaulay Amechi Onuigbo © 2013 Nova Science Publishers, Inc. Chapter 12 MOLECULAR MECHANISMS AND PHARMACOLOGICAL IMPLICATIONS OF MMP-9 INHIBITION BY ACE INHIBITORS Daisuke Yamamoto PhD  1 , Shinji Takai 2 and Merry L. Lindsey 3 1 Biomedical Computation Center 2 Department of Pharmacology, Osaka Medical College, Takatsuki, Osaka, Japan 3 San Antonio Cardiovascular Proteomics Center and Jackson Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, US ABSTRACT Angiotensin converting enzyme (ACE) is well-known as a Zn metalloprotease that converts angiotensin-I to angiotensin-II. Since the 1970’s, ACE inhibitors have been designed to target the ACE active site and have clinically been used as anti-hypertension drugs. Several ACE inhibitors have also been documented to prevent remodeling of the extracellular matrix (ECM) in the setting of myocardial infarction (MI), but it is not clear whether the entirety of this effect is due to angiotensin-II inhibiting functions. Matrix metalloproteinase (MMP)-9, also a Zn dependent protease, is known as one of the key effectors of ECM remodeling, and has a substrate specificity portfolio that is significantly different from ACE. MMP-9 digests type IV collagen as well as several inflammatory proteins. MMP-9 levels increase after MI in humans and animal models, and cardiac dysfunction and mortality after MI are suppressed by MMP-9 inhibitors and in MMP-9 null mice. In addition, recent reports that ACE inhibitors inhibit MMP-9 in an in vitro assay system and in infarcted left ventricles led us to postulate direct interactions between ACE inhibitors and MMP-9. In this review article, we will discuss the molecular  Corresponding author: Daisuke Yamamoto, Ph.D. E-mail: center@art.osaka-med.ac.jp. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.