Genetic Strategies to Elucidate the Roles of Matrix Metalloproteinases in Atherosclerotic Plaque Growth and Stability

A. C. Newby
2005 Circulation Research  
M atrix metalloproteinases (MMPs) are a family of approximately 30 structurally related Zn 2ϩ endopeptidases that each degrades several extracellular matrix (ECM) proteins as well as nonmatrix substrates. 1 Although membrane-type MMPs are integral membrane proteins, most MMPs are secreted or confined to the pericellular environment by binding to surface receptors. Their activity is tightly controlled by regulating transcription and translation of genes and, in a few cases, by packaging and
more » ... packaging and secretion from vesicles, by activation of proforms, and by binding to 4 tissue inhibitors of MMPs. 1 As shown in the Figure, the role of MMPs includes degradation of ECM structural proteins; for example, MMP-1, MMP-8, MMP-13, and MMP-14 cleave type I and III collagens, and MMP-9 and MMP-12 actively degrade elastin. This is probably necessary for vessel wall remodeling and invasion of artery walls by immunoinflammatory cells. Whereas MMP activity should reduce the amount of ECM and therefore limit atherosclerotic plaque growth, locally dysregulated MMP activity could weaken and cause mechanical failure of plaque caps, causing myocardial infarctions (MIs) or strokes, depending on the location. 2,3 Consistent with this, MMP-1 and MMP-13 have been colocalized with epitopes of cleaved collagen in the vulnerable shoulder regions of atherosclerotic plaques. 4 MMPs 2 and 9 also cleave matrix proteins (eg, basement membrane type IV collagen) and nonmatrix substrates (eg, CD-44, cadherins), which, with MMP-14, promote migration, proliferation, and viability of vascular smooth muscle cells, processes expected to favor plaque-cap stability (see Figure) . 3 The same MMPs also influence endothelial loss, repair, and angiogenesis, which could have complex consequences for plaque-cap stability. Actions of MMPs on endothelial cells could contribute to plaque-surface erosion, which also precipitates MI. Given the large number of MMP genes and the potential complexity of their impact on plaque stability, it is not surprising that studies of broad-spectrum MMP inhibitors have so far failed to clarify their role. In experimental models, such inhibitors alter the kinetics (but not extent) of intima formation after balloon injury and do not appear to change atherosclerotic plaque growth. 2,3 Clinical studies failed to show effects of MMP inhibitors on in-stent restenosis in the Brilliant registry or on unstable coronary events in a small pilot trial. 5 Genetic manipulations hold a high potential for elucidating the importance of individual MMPs and therefore providing a rationale for therapy targeted to individual MMPs. Complementary approaches include knockout and transgenic experiments in mice and genetic epidemiological studies, such as that by Pearce et al 6 in this issue of Circulation Research, which relates functional gene polymorphisms to the incidence of disease in humans. Genetic manipulation of apolipoprotein E knockout mice has been widely used to study the function of MMPs, although important differences in dietary regime, background strain, and site of investigation hamper direct comparison among studies. For example, MMP-1 overexpression in macrophages led to smaller, less advanced plaques. 7 These findings imply a protective effect on lesion development but do not rule out a role in rupture of advanced plaques. Deletion of MMP-3 accelerated plaque development in thoracic aortas and brachiocephalic arteries. 8,9 However, whereas MMP-3 knockout reduced inflammation and aneurysm formation in the aorta, 8 it increased inflammation and gave a more unstable plaque phenotype in the brachiocephalic artery. 9 Both studies 8,9 therefore concur that MMP-3 reduces plaque progression but imply opposite effects on plaque stability. In the only available study, deletion of MMP-7 had no effect on plaque growth or stability in the brachiocephalic artery. 9 Deletion of MMP-9 reduced atherosclerosis and microaneurysm formation in the aorta 10 but caused larger, less stable plaques in the brachiocephalic artery. 9 Hence, MMP-9 was found to promote plaque growth and instability in the aorta but to prevent both in the brachiocephalic artery. Deletion of MMP-12 produced more consonant findings; it prevented internal elastic lamina degradation in the aorta 10 and produced smaller more stable lesions in the brachiocephalic artery. 9 In summary, the available evidence suggests that MMP-1 reduces lesion progression, whereas MMP-12 promotes bigger less stable lesions. MMP-3 inhibits lesion growth but plaques appear to be either more or less stable depending on the site. The effects of MMP-9 are ambivalent in the different models. Genetic studies in humans require the identification of reasonably common and functional polymorphisms that can be evaluated in well-characterized patient groups. As with the genetic studies in mice convergence of results between different studies is not always evident, but where it occurs, it
doi:10.1161/01.res.0000193565.23357.c0 pmid:16284186 fatcat:raflyk6p2rh3hft5ancg34vxrm