Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation. Correlation with ischaemic events.
Purified active matrix metalloproteinase-2 (MMP-2) is able to promote platelet aggregation. We aimed to assess the role of MMP-2 expressed in atherosclerotic plaques in the platelet-activating potential of human carotid plaques and its correlation with ischaemic events. Carotid plaques from 81 patients undergoing endarterectomy were tested for pro-MMP-2 and TIMP-2 content by zymography and ELISA. Plaque extracts were incubated with gel-filtered platelets from healthy volunteers for 2 minutes before the addition of a subthreshold concentration of thrombin receptor activating peptide-6 (TRAP-6) and aggregation was assessed. Moreover, platelet deposition on plaque extracts immobilised on plastic coverslips under high shear-rate flow conditions was measured. Forty-three plaque extracts (53%) potentiated platelet aggregation (+233 ± 26.8%), an effect prevented by three different specific MMP-2 inhibitors (inhibitor II, TIMP-2, moAb anti-MMP-2). The pro-MMP-2/TIMP-2 ratio of plaques potentiating platelet aggregation was significantly higher than that of plaques not potentiating it (3.67 ± 1.21 vs 1.01 ± 0.43, p<0.05). Moreover, the platelet aggregation-potentiating effect, the active-MMP-2 content and the active MMP-2/pro-MMP-2 ratio of plaque extracts were significantly higher in plaques from patients who developed a subsequent major cardiovascular event. In conclusion, atherosclerotic plaques exert a prothrombotic effect by potentiating platelet activation due to their content of MMP-2; an elevated MMP-2 activity in plaques is associated with a higher rate of subsequent ischaemic cerebrovascular events.
Massimo
M
Lenti
Emanuela
E
Falcinelli
Marcella
M
Pompili
Paola
P
de Rango
Valentina
V
Conti
Giuseppe
G
Guglielmini
Stefania
S
Momi
Teresa
T
Corazzi
Giuseppe
G
Giordano
Paolo Gresele, MD, PhD, Dept. of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Via E. Dal Pozzo, 06126 Perugia, Italy, Tel.: +39/075 5783989, Fax: +39/075 5716083, E-mail: paolo.gresele@unipg.it.
Paolo
P
Gresele
D002545:Brain Ischemia / Q000097:blood / Q000201:enzymology / Q000209:etiology; D002340:Carotid Artery Diseases / Q000097:blood* / Q000150:complications / Q000201:enzymology*; D004792:Enzyme Precursors / Q000502:physiology; D018093:Gelatinases / Q000502:physiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008955:Models, Cardiovascular; D058226:Plaque, Atherosclerotic / Q000097:blood* / Q000150:complications / Q000201:enzymology*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology
D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; C069860:progelatinase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
Atherosclerotic plaques; TIA/stroke; biomarker; matrix metalloproteinases; platelets