Matrix metalloproteinase-2 on activated platelets triggers endothelial PAR-1 initiating atherosclerosis.

Abstract

Platelets participate in atherogenesis with mechanisms not yet fully clarified. Vascular wall MMP-2 is involved in the arterial remodelling accompanying atherosclerosis. Platelets contain and release MMP-2 but no informations are available on its role in atherosclerotic lesion formation. We generated double knockout mice lacking the LDL receptor and MMP-2 only in circulating blood cells showing that they develop significantly lesser femoral intima thickening after photochemical-induced arterial damage and atherosclerotic lesions in the aorta, measured by the en face method, after 4 months of atherogenic diet. Moreover, repeated transfusions of autologous-activated platelets in LDLR-/- mice on atherogenic diet significantly enhanced the extension of aortic atherosclerotic lesions while transfusion of activated platelets from MMP-2-/- mice did not. In vitro coincubation studies showed that platelet-derived MMP-2 plays a pivotal role in the development and progression of atherosclerosis through a complex cross-talk between activated platelets, monocyte/macrophages, and endothelial cells. Translational studies in patients with CAD and chronic HIV infection showed that platelet surface expression of MMP-2 highly significantly correlated with the degree of carotid artery stenosis. We show a previously unknown mechanism of the pathway through which platelets expressing MMP-2 trigger the initial phases of atherosclerosis and provide a mechanism showing that they activate endothelial PAR-1 triggering endothelial p38MAPK signalling and the expression of adhesion molecules. The development of drugs blocking selectively platelet MMP-2 or its expression may represent a new approach to the prevention of atherosclerosis.