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. Our study demonstrates that platelet-derived MMP-2 plays a pivotal role in the very early phases of atherogenesis in hypercholesterolemic mice. Circulating activated platelets expressing MMP-2 on their surface interact with PAR-1 of endothelial cells triggering signal transduction and activation with the consequent exposure of adhesion molecules (i.e. VCAM-1), the latter in turn facilitate the adhesion and transmigration of monocytes through the endothelial monolayer ultimately leading to atheroma formation. The interaction between MMP-2 expressed by activated platelets and endothelial cell PAR-1 may represent a novel therapeutic target for the prevention of atherosclerosis.

Blood platelets are indubitably one of the wonders of the world, whether the first of the eight may be a matter of debate, but they certainly are. Compared with all other cells they are much smaller and, like few others, devoid of a nucleus but despite this, they are extremely complex and provided with multiple functions [...].

Aim of the present study was to compare the lipid-lowering, antithrombotic and antiatherogenic properties of NCX-6550, nitropravastatin, a nitric-oxide donating derivative of pravastatin, with those of pravastatin in hypercholesterolemic mice. LDL receptor-deficient mice (LDLR–/–) on a normal diet (ND) showed enhanced cholesterol levels as compared to wild type (WT) mice (6.8±1.2 mmol/L and 2.8±0.82 mmol/L, respectively). High fat diet (HFD) induced a large enhancement of cholesterolemia in LDLR–/– mice (23.7±5.7 mmol/L, p<0.0001 vs LDLR–/– ND and WT mice. Treatment with NCX 6550 (48 mg/kg), but not with equimolar pravastatin, reduced cholesterol in LDLR–/–HFD. Platelet adhesion to collagen under high shear rate (3000 sec–1) was significantly higher in LDLR–/– than in normal mice, and further enhanced in LDLR–/–HFD (-27%, p<0.0001 vs untreated). NCX 6550 (48 mg/kg), but not pravastatin, reduced platelet adhesion, especially in LDLR–/–HFD. U46619-induced platelet aggregation ex vivo was also inhibited by NCX 6550 (48 mg/kg) but not by the parent compound. Finally, photochemically-induced acute (1 hr) femoral artery thrombosis and delayed (21 days) intimal thickening was assessed. Thrombus size was larger in LDLR–/– on HFD than in normocholesterolemic mice (0.46±0.04 vs 0.18±0.08 mg) and it was reduced by NCX 6550 (48 mg/kg) (0.08±0.02 mg, p<0.0001), but not by pravastatin (0.4±0.01 mg p=NS). Intimal thickening was greater in hypercholesterolemic than in normal mice (I/M normal=0.53±0.16, LDLR–/–=1.1±0.15, LDLR–/–HFD=1.75 ±0.25). Both NCX 6550 and pravastatin reduced intimal thickening in normal (-95% and -74.5%, respectively) and LDLR–/– mice (-98% and -91%), while in strongly hyperlipidemic animals (LDLR–/–HFD) NCX 6550 was more effective than pravastatin (-98% vs -65%, p<0.0001). NCX 6550 shows greater antithrombotic and antiatherogenic activity than pravastatin in highly hypercholesterolemic mice.