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Thromb Haemost 2014; 111(06): 1089-1101
DOI: 10.1160/TH13-07-0588
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation

Correlation with ischaemic events
Massimo Lenti
1   Division of Vascular and Endovascular Surgery, Hospital S. M. Misericordia, Perugia, Italy
,
Emanuela Falcinelli
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Marcella Pompili
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Paola De Rango
1   Division of Vascular and Endovascular Surgery, Hospital S. M. Misericordia, Perugia, Italy
,
Valentina Conti
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Giuseppe Guglielmini
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Stefania Momi
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Teresa Corazzi
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
,
Giuseppe Giordano
1   Division of Vascular and Endovascular Surgery, Hospital S. M. Misericordia, Perugia, Italy
,
Paolo Gresele
2   Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
› Institutsangaben Financial support: This study was supported in part by a grant from Fondazione Cassa di Risparmio di Perugia (project n. 2011.0137.021) and by a gratuity from Banca d′Italia, Perugia Branch (prot 0557797/12) to P.G.
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Publikationsverlauf

Received: 19. Juli 2013

Accepted after major revision: 21. Februar 2013

Publikationsdatum:
21. November 2017 (online)

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Summary

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.

Keywords

Atherosclerotic plaques - biomarker - matrix metalloproteinases - platelets - TIA/stroke

 

  • References

  • 1 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809.
    CrossrefPubMedGoogle Scholar
  • 2 Lombardo A, Biasucci LM, Lanza GA. et al. Inflammation as a possible link between coronary and carotid plaque instability. Circulation 2004; 109: 3158-3163.
    CrossrefPubMedGoogle Scholar
  • 3 Sukhova GK, Schönbeck U, Rabkin E. et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 1999; 99: 2503-2509.
    CrossrefPubMedGoogle Scholar
  • 4 Turu MM, Krupinski J, Catena E. et al. Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound. Atherosclerosis 2006; 187: 161-169.
    CrossrefPubMedGoogle Scholar
  • 5 Heo SH, Cho CH, Kim HO. et al. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of matrix metalloproteinases 2 and 9. Clin Neurol 2011; 07: 69-76.
    CrossrefPubMedGoogle Scholar
  • 6 Sluijter JP, Pulskens WP, Schoneveld AH. et al. Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 2006; 37: 235-239.
    CrossrefPubMedGoogle Scholar
  • 7 Li Z, Li L, Zielke HR. et al. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am J Pathol 1996; 148: 121-128.
    PubMedGoogle Scholar
  • 8 Shah PK, Falk E, Badimon JJ. et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 1995; 92: 1565-1569.
    PubMedGoogle Scholar
  • 9 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90: 251-262.
    CrossrefPubMedGoogle Scholar
  • 10 Busti C, Falcinelli E, Momi S. et al. Matrix metalloproteinases and peripheral arterial disease. Intern Emerg Med 2010; 05: 13-25.
    CrossrefPubMedGoogle Scholar
  • 11 Sawicki G, Salas E, Murat J. et al. Release of gelatinase A during platelet activation mediates aggregation. Nature 1997; 386: 616-619.
    CrossrefPubMedGoogle Scholar
  • 12 Falcinelli E, Guglielmini G, Torti M. et al. Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-2 on platelet aggregation. J Thromb Haemost 2005; 03: 2526-2535.
    CrossrefPubMedGoogle Scholar
  • 13 Santos-Martinez MJ, Medina C, Gilmer JF. et al. Matrix metalloproteinases in platelet function: coming of age. J Thromb Haemost 2008; 06: 514-516.
    CrossrefPubMedGoogle Scholar
  • 14 Momi S, Falcinelli E, Giannini S. et al. Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo. J Exp Med 2009; 206: 2365-2379.
    CrossrefPubMedGoogle Scholar
  • 15 Gresele P, Falcinelli E, Loffredo F. et al. Platelets release matrix metalloproteinase-2 in the coronary circulation of patients with acute coronary syndromes: possible role in sustained platelet activation. Eur Heart J 2011; 32: 316-325.
    CrossrefPubMedGoogle Scholar
  • 16 Gresele P, Falcinelli E, Momi S. Potentiation and priming of platelet activation: a potential target for antiplatelet therapy. Trends Pharmacol Sci 2008; 29: 352-360.
    CrossrefPubMedGoogle Scholar
  • 17 Reininger AJ, Bernlochner I, Penz SM. et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol 2010; 55: 1147-1158.
    CrossrefPubMedGoogle Scholar
  • 18 Penz SM, Reininger AJ, Toth O. et al. Glycoprotein Ibalpha inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques. Thromb Haemost 2007; 97: 435-443.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-599.
    CrossrefPubMedGoogle Scholar
  • 20 Falcinelli E, Giannini S, Boschetti E. et al. Platelets release active matrix metallo-proteinase-2 in vivo in humans at a site of vascular injury: lack of inhibition by aspirin. Br J Haematol 2007; 138: 221-230.
    CrossrefPubMedGoogle Scholar
  • 21 Cecchetti L, Tolley ND, Michetti N. et al. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 2011; 118: 1903-1911.
    CrossrefPubMedGoogle Scholar
  • 22 Vezza R, Roberti R, Nenci GG. et al. Prostaglandin E2 potentiates platelet aggregation by priming protein kinase C. Blood 1993; 82: 2704-2713.
    CrossrefPubMedGoogle Scholar
  • 23 Ikejiri M, Bernardo MM, Bonfil RD. et al. Potent mechanism-based inhibitors for matrix metalloproteinases. J Biol Chem 2005; 280: 33992-34002.
    CrossrefPubMedGoogle Scholar
  • 24 Gresele P, Marzotti S, Guglielmini G. et al. Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent. Diabetes Care 2010; 33: 1262-1268.
    CrossrefPubMedGoogle Scholar
  • 25 Momi S, Impagnatiello F, Guzzetta M. et al. NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. Eur J Pharmacol 2007; 570: 115-124.
    CrossrefPubMedGoogle Scholar
  • 26 Sixma JJ, de Groot PG, van Zanten H. et al. A new perfusion chamber to detect platelet adhesion using a small volume of blood. Thromb Res 1998; 92: S43-46.
    CrossrefPubMedGoogle Scholar
  • 27 Momi S, Monopoli A, Alberti PF. et al. Nitric oxide enhances the anti-inflammatory and antiatherogenic activity of atorvastatin in a mouse model of accelerated atherosclerosis. Cardiovasc Res 2012; 94: 428-438.
    CrossrefPubMedGoogle Scholar
  • 28 Leal S, Diniz C, Sá C. et al. Semiautomated computer-assisted image analysis to quantify 3,3’-diaminobenzidine tetrahydrochloride-immunostained small tissues. Anal Biochem 2006; 357: 137-143.
    CrossrefPubMedGoogle Scholar
  • 29 Penz S, Reininger AJ, Brandl R. et al. Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI. FASEB J 2005; 19: 898-909.
    CrossrefPubMedGoogle Scholar
  • 30 Tanaka A, Shimada K, Sano T. et al. Multiple plaque rupture and C-reactive protein in acute myocardial infarction. J Am Coll Cardiol 2005; 45: 1594-1599.
    CrossrefPubMedGoogle Scholar
  • 31 Fintel DJ. Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options. Vasc Health Risk Manag 2012; 08: 77-89.
    CrossrefPubMedGoogle Scholar
  • 32 Hu YF, Lu TM, Wu CH. et al. Differences in high on-treatment platelet reactivity between intracoronary and peripheral blood after dual anti-platelet agents in patients with coronary artery disease. Thromb Haemost 2013; 110: 124-130.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 33 Yiqin Y, Meilin X, Jie X, Keping Z. Aspirin inhibits MMP-2 and MMP-9 expression and activity through PPARalpha/gamma and TIMP-1-mediated mechanisms in cultured mouse celiac macrophages. Inflammation 2009; 32: 233-241.
    CrossrefPubMedGoogle Scholar
  • 34 Pedersen AK, FitzGerald GA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med 1984; 311: 1206-1211.
    CrossrefPubMedGoogle Scholar
  • 35 Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res 2007; 100: 1673-1685.
    CrossrefPubMedGoogle Scholar
  • 36 Jenkins GM, Crow MT, Bilato C. et al. Increased expression of membrane-type matrix metalloproteinase and preferential localisation of matrix metalloproteinase-2 to the neointima of balloon-injured rat carotid arteries. Circulation 1998; 97: 82-90.
    CrossrefPubMedGoogle Scholar
  • 37 Schulze CJ, Wang W, Suarez-Pinzon WL. et al. Imbalance between tissue inhibitor of metalloproteinase-4 and matrix metalloproteinases during acute myocardial ischaemia-reperfusion injury. Circulation 2003; 107: 2487-2492.
    CrossrefPubMedGoogle Scholar
  • 38 Schneider F, Sukhova GK, Aikawa M. et al. Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques. Circulation 2008; 117: 931-939.
    CrossrefPubMedGoogle Scholar
  • 39 Peeters W, Moll FL, Vink A, van der Spek PJ, de Kleijn DP, de Vries JP, Verheijen JH, Newby AC, Pasterkamp G. Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome. Eur Heart J 2011; 32: 2314-2325.
    CrossrefPubMedGoogle Scholar
  • 40 Choudhary S, Higgins CL, Chen IY, Reardon M, Lawrie G, Vick 3rd GW, Karmonik C, Via DP, Morrisett JD. Quantitation and localisation of matrix metalloproteinases and their inhibitors in human carotid endarterectomy tissues. Arterioscler Thromb Vasc Biol 2006; 26: 2351-2358.
    CrossrefPubMedGoogle Scholar
  • 41 van Zanten GH, de Graaf S, Slootweg PJ. et al. Increased platelet deposition on atherosclerotic coronary arteries. J Clin Invest 1994; 93: 615-632.
    CrossrefPubMedGoogle Scholar
  • 42 Galt SW, Lindemann S, Allen L. et al. Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function. Circ Res 2002; 90: 1093-1099.
    CrossrefPubMedGoogle Scholar
  • 43 Sheu JR, Fong TH, Liu CM. et al. Expression of matrix metalloproteinase-9 in human platelets: regulation of platelet activation in in vitro and in vivo studies. Br J Pharmacol 2004; 143: 193-201.
    CrossrefPubMedGoogle Scholar
  • 44 Fernandez-Patron C, Martinez-Cuesta MA, Salas E. et al. Differential regulation of platelet aggregation by matrix metalloproteinases-9 and −2. Thromb Haemost 1999; 82: 1730-1735.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 45 Hans CP, Feng Y, Naura AS. et al. Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy. Cardiovasc Pathol 2011; 20: e57-68.
    CrossrefPubMedGoogle Scholar
  • 46 Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol 2003; 41: 7S-14S.
    CrossrefPubMedGoogle Scholar
  • 47 Stone GW, Maehara A, Lansky AJ. et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011; 364: 226-235.
    CrossrefPubMedGoogle Scholar
  • 48 Slevin M, Wang Q, Font MA. et al. Atherothrombosis and plaque heterology: different location or a unique disease?. Pathobiology 2008; 75: 209-225.
    CrossrefPubMedGoogle Scholar
  • 49 Newby AC. Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol 2012; 56: 232-244.
    CrossrefPubMedGoogle Scholar