A prominent role of mmp-10 in atherosclerosis associated with vascular calcification

Abstract

We have investigated the role of metalloproteinase-10 (MMP-10) in the atherothrombotic process, using in vivo and in vitro experimental approaches, and explored its possible association with vascular calcification. Aortic MMP-10 expression was observed in the atherosclerotic lesion of apolipoprotein E-/- (apoE-/-), but not in the healthy vascular wall of wild type mice, colocalizing with macrophage-like cells. In apoE-/- mice, lack of functional MMP-10 was associated with reduced lesion size in three different vascular beds, less vascular calcification, plaque rupture and macrophage content, and increased vascular smooth muscle cells, indicating a more stable plaque phenotype. We have also shown that MMP-10 is involved in human atherosclerosis: human atherosclerotic plaques express and secrete MMP-10 to the medium, particularly calcified atheromas. Circulating MMP-10 levels are associated with coronary calcium in subclinical atherosclerosis, a marker of cardiovascular risk. Chronic kidney disease patients present increased serum MMP-10 levels associated with the severity of atherosclerosis and vascular calcification. In vitro, MMP-10 accelerates endothelial wound healing by promoting human ECs migration and proliferation. Proinflammatory stimuli induce MMP-10 expression in endothelium, macrophages and VSMCs. Finally, we have demonstrated that while aortic VSMCs from MMP-10 deficient mice exhibit reduces calcium deposition, MMP-10 induces a calcifying phenotype in murine and human VSMCs. In summary, these findings reveal that MMP-10 plays a crucial role in different stages of the atherosclerotic process by promoting plaque inflammation and increased calcification. Circulating MMP-10 concentration may represent a new risk marker of atherosclerosis, a predictor of cardiovascular events.