Matrix metalloproteinases and peripheral arterial disease

Matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix, are emerging as important modulators of atherothrombosis. MMPs are produced by inflammatory cells; some of them are also released by activated platelets and play a crucial role in the remodeling processes, leading to atherosclerotic plaque formation, plaque rupture, arterial aneurysm development, and critical limb ischemia. Independent from their matrix degrading activity, MMPs also regulate some cell functions relevant to atherothrombosis, such as platelet activation, neutrophil activation, and vascular reactivity. Plasma levels of some MMPs are increasingly being recognized as a biomarker of atherosclerosis and cardiovascular risk. In peripheral arterial disease, MMPs have been shown to be involved in angiogenesis, arteriogenesis, and the development of arterial calcifications. Increased plasma levels of some MMPs (MMP-2, MMP-9) have been correlated with PAD development and severity. Single nucleotide polymorphisms of the genes encoding for some MMPs have also been associated with the risk of developing peripheral arterial disease and critical limb ischemia. Large prospective observational studies are needed to further demonstrate the role of MMPs in PAD. In perspective, pharmacologic targeting of the expression or activity of MMPs may represent a novel, attractive approach for the treatment of peripheral arterial disease.