New Insights Into the World of Matrix Metalloproteinases

The article by Carrel et al1 in the present issue of Circulation provides remarkable new insights into the matrix metalloproteinases (MMPs) and their effects on the remodeling of the vascular system in aortic atherosclerotic and aneurysmal lesions. The MMPs constitute a family of endopeptidases that have in common the presence of zinc in their active site, a dependency on Ca2+ for their activity, and the ability to react with specific tissue inhibitors of metalloproteinases (TIMPs) to form enzymatically inactive complexes. The MMPs show a wide range of specificity for different substrates, including native and partially degraded fibrillar collagens, basement membrane collagens, proteoglycans, elastin, and fibronectin.2 The ability of certain MMPs, such as MMP-2, MMP-3, MMP-9, and MMP-12, to hydrolyze elastin are of particular importance in terms of their effects on the vasculature. The “classic” MMPs are synthesized in an enzymatically inactive form, which requires activation by single or multiple steps, as well as by multiple mechanisms, in order to uncover their active site and thereby become biologically active. The “novel” MMPs (known as membrane-type matrix metalloproteinases or MT-MMPs) are synthesized in an active form and play important roles in the proteolytic activation of the classic MMPs.3 The MMPs are synthesized by a variety of parenchymal cells, connective tissue cells, and inflammatory cells.2See p 477 The importance of MMPs in the pathogenesis of vascular disorders increasingly is being recognized, particularly with respect to atherosclerotic lesions, aortic and cerebral aneurysm, and Marfan syndrome.4 In normal vascular tissues, endothelial cells, medial smooth muscle cells, and adventitial connective tissue cells are the main sources of MMPs, most of which are present in inactive form.5 However, the macrophages and other types of infiltrating cells are known to be important sources of MMPs in a wide variety of …