Matrix metalloproteinase inhibition therapy for vascular diseases

The matrix metalloproteinases (MMPs) are 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms, as substantiated in clinical and mouse knockout and transgenic studies. Prominent counterbalancing roles for MMPs in tissue destruction and repair emerge from these experiments. Naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesised small molecular weight MMP inhibitors (MMPis) and inhibitory antibodies have all shown effects in animal models of vascular disease but only doxycycline has been evaluated extensively in patients. A limitation of broad specificity MMPis is that they prevent both matrix degradation and tissue repair functions of different MMPs. Hence MMPis with more restricted specificity have been developed and recent studies in models of atherosclerosis accurately replicate the phenotypes of the corresponding gene knockouts. This review documents the established actions of MMPs and their inhibitors in vascular pathologies and considers the prospects for translating these findings into new treatments.