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Factor Seven Activating Protease (FSAP) expression in human monocytes and accumulation in unstable coronary atherosclerotic plaques

      Abstract

      Objective

      The Factor Seven Activating Protease (FSAP) is known to influence fibrinolysis and to play a critical role in the inhibition of vascular smooth muscle cell (VSMC) proliferation and migration as well as neointima formation. In order to define the role of FSAP in vascular pathophysiology we have investigated the expression of FSAP protein and mRNA in human vascular cells and coronary atherosclerotic plaques with defined clinical features.

      Methods and results

      Directional coronary atherectomy (DCA) specimens from 40 lesions were analyzed for FSAP antigen and mRNA expression. Higher level of FSAP mRNA (p < 0.001) as well as FSAP immunostaining (p < 0.005) was observed in patients with acute coronary syndromes compared to patients with stable angina pectoris. FSAP antigen was found to be focally accumulated in hypocellular and lipid-rich areas within the necrotic core of atherosclerotic plaques. FSAP was also co-localized with CD11b/CD68 expressing cells in macrophage-rich shoulder regions of the plaques. Monocyte-derived macrophages expressed FSAP in vitro and this was further induced by pro-inflammatory mediators.

      Conclusions

      FSAP accumulation in coronary atherosclerotic lesions is due to either local synthesis by monocytes/macrophages, or uptake from the plasma due to plaque hemorrhage. The higher expression of FSAP in unstable plaques suggests that it may destabilise plaque through reducing VSMC proliferation/migration and altering the hemostatic balance.

      Keywords

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      References

        • Choi-Miura N.H.
        • Tobe T.
        • Sumiya J.
        • et al.
        Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator.
        J Biochem. 1996; 119: 1157-1165
        • Römisch J.
        • Feussner A.
        • Vermöhlen S.
        • Stöhr H.A.
        A protease isolated from human plasma activating Factor VII independent of tissue factor.
        Blood Coagul Fibrinolysis. 1999; 10: 471-479
        • Römisch J.
        • Vermöhlen S.
        • Feussner A.
        • Stöhr H.A.
        The FVII activating protease cleaves single-chain plasminogen activators.
        Haemostasis. 1999; 29: 292-299
        • Willeit J.
        • Kiechl S.
        • Weimer T.
        • et al.
        Marburg I polymorphism of factor VII.activating protease: a prominent risk predictor of carotid stenosis.
        Circulation. 2003; 107: 667-670
        • Ireland H.
        • Miller G.J.
        • Webb K.E.
        • Cooper J.A.
        • Humphries S.E.
        The factor VII activating protease G511E (Marburg) variant and cardiovascular risk.
        Thromb Haemost. 2004; 92: 986-992
        • Hoppe B.
        • Tolou F.
        • Radtke H.
        • et al.
        Marburg I polymorphism of factor VII activating protease is associated with idiopathic venous thromboembolism.
        Blood. 2005; 105: 1549-1551
        • Roemisch J.
        • Feussner A.
        • Nerlich C.
        • Stoehr H.A.
        • Weimer T.
        The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP).
        Blood Coagul Fibrinolysis. 2002; 13: 433-441
        • Kannemeier C.
        • Al-Fakhri N.
        • Preissner K.T.
        • Kanse S.M.
        Factor VII activating protease (FSAP) inhibits growth factor-mediated cell proliferation and migration of vascular smooth muscle cells.
        FASEB J. 2004; 18: 728-730
        • Sedding D.
        • Daniel J.M.
        • Muhl L.
        • et al.
        Factor VII activating protease inhibits neointima formation and the G534E polymorphism is associated with cardiovascular risk due to a loss of this activity.
        J Exp Med. 2006; 203: 2801-2807
        • Abdelmegui A.E.
        • Ellis S.G.
        • Sapp S.K.
        • et al.
        Directional atherectomy in unstable angina.
        J Am Coll Cardiol. 1994; 24: 46-54
        • Simonton C.A.
        • Leon M.B.
        • Baim D.S.
        • et al.
        ‘Optimal’ directional coronary atherectomy: final results of the Optimal Atherectomy Restenosis Study (OARS).
        Circulation. 1998; 97: 332-339
        • Stary H.C.
        Natural history and histological classification of atherosclerotic lesion.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1177-1178
        • Holschermann H.
        • Bohle R.M.
        • Zeller H.
        • et al.
        In situ detection of tissue factor within the coronary intima in rat cardiac allograft vasculopathy.
        Am J Pathol. 1999; 154: 211-220
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
        Methods. 2001; 25: 402-408
        • Fink L.
        • Kinfe T.
        • Seeger W.
        • et al.
        Immunostaining for cell picking and real-time mRNA quantitation.
        Am J Pathol. 2000; 157: 1459-1466
        • Lutz M.B.
        • Schuler G.
        Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?.
        Trends Immunol. 2002; 23: 445-449
        • Jaffe Eric A.
        • Nachman Ralph L.
        • Becker Carl G.
        • Minick Richard C.
        Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria.
        J Clin Invest. 1973; 52: 2745-2756
        • Hansson G.K.
        Immune mechanisms in atherosclerosis.
        Atheroscler Thromb Vasc Biol. 2001; 21: 1876-1890
        • Felton C.V.
        • Crook D.
        • Davies M.J.
        • Oliver M.F.
        Relation of plaque lipid composition and morphology to the stability of human aortic plaques.
        Atheroscler Thromb Vasc Biol. 1997; 17: 1337-1345
        • Salame M.Y.
        • Samani N.J.
        • Masood I.
        • deBono D.P.
        Expression of the plasminogen activator system in the human vascular wall.
        Atherosclerosis. 2000; 152: 19-28
        • Allaire E.
        • Hasenstab D.
        • Kenagy R.D.
        • et al.
        Prevention of aneurysm development and rupture by local overexpression of plasminogen activator inhibitor-1.
        Circulation. 1998; 98: 249-255
        • Schwartz S.M.
        • Virmani R.
        • Rosenfeld M.E.
        The good smooth muscle cells in atherosclerosis.
        Curr Atheroscler Rep. 2000; 2: 422-429
        • Virmani R.
        • Kolodgie F.D.
        • Burke A.P.
        • et al.
        Atherosclerotic plaque progression and vulnerability to rupture.
        Atheroscler Thromb Vasc Biol. 2005; 25: 2054-2061
        • Muhl L.
        • Nykjaer A.
        • Wygrecka M.
        • et al.
        Inhibition of PDGF-BB by factor VII activating protease is neutralized by protease nexin-1 and the FSAP-inhibitor complexes are internalized via LRP.
        Biochem J. February 2007; ([Epub ahead of print])