Role of Matrix Metalloproteinases in the Development and Progression of Atherosclerosis

Abstract

Atherosclerosis underlies the majority of cardiovascular diseases and is accepted as a primary cause of mortality worldwide. Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) perform complex roles during the progression and development of atherosclerosis and subsequent plaque instability. Proposed actions of MMPs include extracellular matrix remodeling alongside regulation of vascular cell proliferation, migration and apoptosis including cell types such as monocytes, macrophages and vascular smooth muscle cells. As such, a large body of evidence from both in vitro and in vivo studies has shown that individual MMPs and TIMPs are utilized by distinct cell types to regulate their behavior. Consequently, it is now accepted that some MMPs promote the growth and development of advanced atherosclerotic plaques in experimental models whilst others do not . Similarly, human genetic and pathological findings reveal some MMPs correlate with vulnerable atherosclerotic plaque phenotypes, whereas others associate with stable lesions. Furthermore, broad-spectrum MMP inhibition in both mouse and man has proved ineffective at protecting from atherosclerotic plaque progression and instability. Considering the divergent effects MMPs exert on atherosclerotic lesions, selectively targeting individual deleterious MMPs may serve as a more efficacious therapeutic strategy. For example, our recent data demonstrate that a selective MMP-12 inhibitor retards atherosclerotic plaque progression in the apolipoprotein E (Apoe) mouse atherosclerosis model, whilst also promoting plaque stabilization through reducing monocyte recruitment into plaques whilst augmenting fibrosis. Similar studies have been conducted assessing MMP-13 inhibition. Accordingly, as our knowledge of the complex roles MMPs play during the development, progression and rupture of atherosclerotic plaques expands, new impetus is required for clinical trials evaluating the therapeutic potential of selective MMP inhibition, especially in the context of atherosclerosis.