[Frontiers in Bioscience 13, 2916-2921, January 1, 2008] 2916 Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli Jose A. Rodriguez 1 , Josune Orbe 1 , Sara Martinez de Lizarrondo 1 , Olivier Calvayrac 2 , Cristina Rodriguez 2 , Jose Martinez-Gonzalez 2 , Jose A. Paramo 1 1 Atherosclerosis Research Laboratory, Division of Cardiovascular Sciences. CIMA- University of Navarra. Avda. Pio XII 55, 31008 Pamplona, Spain, 2 Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, C/Antoni Mª Claret 167, 08025 Barcelona, Spain TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Metalloproteinases in atherosclerosis 3.1. MMP structure and function 3.2. MMPs in the atherosclerotic vascular wall 3.3. MMP inhibitors 4. MMP-10 in atherosclerosis 4.1. Inflammation induces endothelial MMP-10 expression 4.2. MMP-10 is expressed in atherosclerotic vessels 4.3. MMP-10 compromises vascular integrity 4.4. Circulating MMP-10 as a biomarker 4.5. Transcriptional regulation of MMP-10 expression 5. Summary and perspectives 6. Acknowledgements 7. References 1. ABSTRACT Atherosclerosis is the common pathophysiologi- cal substrate of ischemic vascular diseases and their thrombotic complications. The unbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) has been hypothesized to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Different MMPs have been assigned relevant roles in the pathology of vascular diseases and MMP-10 (stromelysin-2) has been involved in vascular development and atherogenesis. This article examines the pathophysiological role of MMPs, particularly MMP-10, in the onset and progression of vascular diseases and their regulation by pro-inflammatory stimuli. MMP-10 over- expression has been shown to compromise vascular integrity and it has been associated with aortic aneurysms. MMP-10 is induced by C-reactive protein in endothelial cells, and it is over-expressed in atherosclerotic lesions. Additionally, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and the presence of atherosclerotic plaques. We have cloned the promoter region of the MMP-10 gene and studied the effect of inflammatory stimuli on MMP-10 transcriptional regulation, providing evidences further supporting the involvement of MMP-10 in the pathophysiology of atherothrombosis. 2. INTRODUCTION Atherosclerosis development involves a series of stages in which inflammatory and proteolytic activities are fundamental determining plaque stability and rupture (1). Vulnerable (high risk) plaques are characterized by a big necrotic core, thin fibrous cap and an inflammatory infiltrate mainly composed by monocyte/macrophages, neutrophils and lymphocytes. Atherosclerotic plaque rupture causes 75% mortality after acute myocardial infarction (2). Matrix metalloproteinases (MMPs) are proteolytic enzymes that carry out highly selective cleavage of specific substrates, degrading extracellular matrix (ECM) components and modulating tissue remodeling. MMPs, alone or in combination with the fibrinolytic system, are key factors in vascular remodeling associated to atherosclerosis. It has been assumed that these enzymes favor local cell migration and neointima formation, contributing to atheromatous plaque destabilization (3). Recently, MMP-10 (also known as stromelysin-2) over- expression has been reported in various carcinomas and tumors (4), and it has also been proposed to be involved in vascular pathologies. MMP-10 degrades multiple components of the ECM or stromal connective tissue, such as proteoglycan, laminin, fibronectin, and collagen III and IV (5). MMP-10 has been proposed to participate in