K42	Metalloproteinases in vascular pathology — what we know and what we don't know.
A.Newby
Bristol Heart Institute, University of Bristol, Bristol, GB.

Matrix metalloproteinases (MMPs) are a family of more than 25 secreted or cell membrane attached Zn2+ containing neutral endopeptidases, at least 14 of which occur in vascular cells. Each one has a number of extracellular matrix and non-matrix substrates. They are regulated by transcription, translation, packaging and secretion, activation extracellularly or in the Golgi apparatus, and by binding to four tissue inhibitors of MMPs (TIMPs). Mechanisms can confine MMP activity to the pericellular environment. MMPs share a catalytic domain with the disintegrin metalloproteinases (ADAMs) but are distinguished by gene structure and sensitivity to TIMPs. Endothelial and smooth muscle cells (SMCs), fibroblasts, macrophages and other leukocytes all secrete MMPs in vitro with an interesting hierarchy of expression. MMP-2 and –9, which degrade basement membranes, are easily upregulated but other MMPs that degrade interstitial matrix proteins need inflammatory or immune signals, which are hence potentially more destructive. The mediators responsible in vivo are largely unknown. The following criteria have been developed to judge the importance of MMPs in vascular pathologies 1) upregulation during pathology, 2) over expression mimics pathology, 3) inhibition and knockout reverses the pathology and 4) plausible mechanisms exist. Neointima formation in several models rapidly upregulates MMP-2 and –9 and TIMP gene transfer is inhibitory. From knockout studies both MMP-2 and –9 are necessary for intima formation in mouse carotid arteries. However synthetic MMPs inhibitors failed to prevent neointima formation in experimental and clinical studies. MMPs-2 and –9 are essential for migration of SMC but not for proliferation, even though remodelling of matrix and non-matrix proteins are essential events. It is possible that other protease classes can substitute for the MMPs but this hypothesis lacks definitive verification. Atherosclerosis leads to upregulation of a wide range of MMPs that could mediate a variety of processes including migration, proliferation and death of endothelial, SMC and leukocytes. The net effect could be increased fibrous cap formation or weakening and plaque rupture. Knockout studies with individual MMPs reflect this variety of outcomes. Gene transfer of TIMPs reduces plaque formation in mice but synthetic MMP inhibitors again fail to replicate this effect. How these studies relate to the role of MMPs in human atherosclerosis is unknown but clinical biomarker and genetic epidemiology studies are beginning to shed some light. Prospects and limitations of pharmacotherapy will be considered.

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