Role of matrix metalloproteinases in atherosclerosis

Abstract

Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) play a complex role in the pathogenesis of atherosclerosis and plaque instability. Proposed roles for MMPs included matrix degradation but also regulation of the proliferation, migration and apoptosis of monocytes, macrophages and vascular smooth muscle cells. Accordingly, in vitro and in vivo studies have demonstrated that individual MMPs are utilised by distinct cell types to modulate their behaviour. As a result some MMPs clearly promote plaque growth and development of "vulnerable" morphologies in experimental models but others do not. Likewise some MMPs associate with vulnerable atherosclerotic plaque phenotypes in man, whilst others correlate with stable lesions. This premise is underlined by the fact that in both mouse and man, broad-spectrum MMP inhibition fails to exert beneficial effects on atherosclerotic plaque development and stability. Given that MMPs exert such diversity on atherosclerotic lesions, one therapeutic strategy may be to selectively inhibit those MMPs particularly implicated in adverse plaque phenotypes. An example is our recent use of a selective MMP-12 inhibitor in the apolipoprotein E (Apoe) mouse model. The inhibitor retards progression of established plaques, in part by reducing the recruitment of monocytes into plaques but also by preventing apoptosis of foamcell macrophages and calcification. Consequently, although our understanding of the multifaceted role MMPs play during the development, progression and rupture of atherosclerotic plaques are becoming clearer; the need for selective MMP inhibition is required for the translation of the experimental findings to the clinic.