Arteriosclerosis, Vol 10, 240-245, Copyright © 1990 by American Heart Association

ARTICLES

Lipoprotein(a), fibrin binding, and plasminogen activation

J Loscalzo, M Weinfeld, GM Fless and AM Scanu
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115.

Lipoprotein(a) (Lp[a]) is a complex plasma lipoprotein in which apolipoprotein (apo) B-100 is covalently linked by a disulfide bridge to a unique apolipoprotein, apo(a). The cDNA of apo(a) has recently been isolated and sequenced, and a remarkable homology to human plasminogen has been noted. In this report, we demonstrate that, like plasminogen, Lp(a) binds to fibrin. In addition, Lp(a) competes with plasminogen and tissue-type plasminogen activator for fibrin binding. As a functional consequence of these binding properties, we show that Lp(a) attenuates the fibrin-dependent enhancement of tissue-type plasminogen activator activity against the native substrate, and does so as an uncompetitive inhibitor (Ki = 15 nM). Finally, we show that in a plasma milieu, Lp(a) attenuates clot lysis induced by tissue-type plasminogen activator. None of these effects was noted with low density lipoprotein free of apo(a). These data suggest that Lp(a) influences the fibrinolytic system and probably does so by virtue of the fibrin binding properties conferred by the kringle repeats of apo(a).

This article has been cited by other articles:

				J. Suk Danik, N. Rifai, J. E. Buring, and P. M. Ridker Lipoprotein(a), Hormone Replacement Therapy, and Risk of Future Cardiovascular Events J. Am. Coll. Cardiol., July 8, 2008; 52(2): 124 - 131. [Abstract] [Full Text] [PDF]

				V. Mallika, B. Goswami, and M. Rajappa Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective Angiology, November 1, 2007; 58(5): 513 - 522. [Abstract] [PDF]

				J. Suk Danik, N. Rifai, J. E. Buring, and P. M Ridker Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA, September 20, 2006; 296(11): 1363 - 1370. [Abstract] [Full Text] [PDF]

				T. Tholstrup and S. Samman Postprandial Lipoprotein(a) Is Affected Differently by Specific Individual Dietary Fatty Acids in Healthy Young Men J. Nutr., October 1, 2004; 134(10): 2550 - 2555. [Abstract] [Full Text] [PDF]

				P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]

				T. Uchida, T. Inoue, H. Kamishirado, K. Takayanagi, and S. Morooka Prediction of Short-Term Progression or Regression of Atherosclerotic Coronary Artery Disease by Lipoprotein (a): A Quantitative Coronary Angiographic Study Angiology, November 1, 2003; 54(6): 641 - 646. [Abstract] [PDF]

				H. Muller, A. S. Lindman, A. Blomfeldt, I. Seljeflot, and J. I. Pedersen A Diet Rich in Coconut Oil Reduces Diurnal Postprandial Variations in Circulating Tissue Plasminogen Activator Antigen and Fasting Lipoprotein (a) Compared with a Diet Rich in Unsaturated Fat in Women J. Nutr., November 1, 2003; 133(11): 3422 - 3427. [Abstract] [Full Text] [PDF]

				S. N. Pokrovsky, M. V. Ezhov, L. N. Il'ina, O. I. Afanasieva, V. Y. Sinitsyn, A. A. Shiriaev, and R. S. Akchurin Association of lipoprotein(a) excess with early vein graft occlusions in middle-aged men undergoing coronary artery bypass surgery J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1071 - 1075. [Abstract] [Full Text] [PDF]

				G. Tsurupa, B. Ho-Tin-Noe, E. Angles-Cano, and L. Medved Identification and Characterization of Novel Lysine-independent Apolipoprotein(a)-binding Sites in Fibrin(ogen) {alpha}C-domains J. Biol. Chem., September 26, 2003; 278(39): 37154 - 37159. [Abstract] [Full Text] [PDF]

				M. A. Hancock, M. B. Boffa, S. M. Marcovina, M. E. Nesheim, and M. L. Koschinsky Inhibition of Plasminogen Activation by Lipoprotein(a): CRITICAL DOMAINS IN APOLIPOPROTEIN(a) AND MECHANISM OF INHIBITION ON FIBRIN AND DEGRADED FIBRIN SURFACES J. Biol. Chem., June 20, 2003; 278(26): 23260 - 23269. [Abstract] [Full Text] [PDF]

				M. von Depka, U. Nowak-Gottl, R. Eisert, C. Dieterich, M. Barthels, I. Scharrer, A. Ganser, and S. Ehrenforth Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism Blood, November 15, 2000; 96(10): 3364 - 3368. [Abstract] [Full Text] [PDF]

				J. Xia, L. F. May, and M. L. Koschinsky Characterization of the basis of lipoprotein [a] lysine-binding heterogeneity J. Lipid Res., October 1, 2000; 41(10): 1578 - 1584. [Abstract] [Full Text]

				L S Tam, E K Li, C W. Lam, and B Tomlinson Hydroxychloroquine has no significant effect on lipids and apolipoproteins in Chinese systemic lupus erythematosus patients with mild or inactive disease Lupus, July 1, 2000; 9(6): 413 - 416. [Abstract] [PDF]

				K. Miwa, K. Nakagawa, N. Yoshida, Y. Taguchi, and H. Inoue Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in patients with coronary vasospasm J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1200 - 1205. [Abstract] [Full Text] [PDF]

				K. Bdeir, W. Cane, G. Canziani, I. Chaiken, J. Weisel, M. L. Koschinsky, R. M. Lawn, P. G. Bannerman, B. S. Sachais, A. Kuo, et al. Defensin Promotes the Binding of Lipoprotein(a) to Vascular Matrix Blood, September 15, 1999; 94(6): 2007 - 2019. [Abstract] [Full Text] [PDF]

				F. Kronenberg, M. F. Kronenberg, S. Kiechl, E. Trenkwalder, P. Santer, F. Oberhollenzer, G. Egger, G. Utermann, and J. Willeit Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis : Prospective Results From the Bruneck Study Circulation, September 14, 1999; 100(11): 1154 - 1160. [Abstract] [Full Text] [PDF]

				K. J. Harjai Potential New Cardiovascular Risk Factors: Left Ventricular Hypertrophy, Homocysteine, Lipoprotein(a), Triglycerides, Oxidative Stress, and Fibrinogen Ann Intern Med, September 7, 1999; 131(5): 376 - 386. [Abstract] [Full Text] [PDF]

				U. Nowak-Gottl, R. Junker, M. Hartmeier, H.-G. Koch, N. Munchow, G. Assmann, and A. von Eckardstein Increased Lipoprotein(a) Is an Important Risk Factor for Venous Thromboembolism in Childhood Circulation, August 17, 1999; 100(7): 743 - 748. [Abstract] [Full Text] [PDF]

				A. Wehinger, A. Kastrati, S. Elezi, H. Baum, S. Braun, F.-J. Neumann, and A. Schomig Lipoprotein(a) and coronary thrombosis and restenosis after stent placement J. Am. Coll. Cardiol., March 15, 1999; 33(4): 1005 - 1012. [Abstract] [Full Text] [PDF]

				S. Allen, S. Khan, S.-p. Tam, M. Koschinsky, P. Taylor, and M. Yacoub Expression of adhesion molecules by Lp(a): a potential novel mechanism for its atherogenicity FASEB J, December 1, 1998; 12(15): 1765 - 1776. [Abstract] [Full Text]

				X. J. Lou, N. W. Boonmark, F. T. Horrigan, J. L. Degen, and R. M. Lawn Fibrinogen deficiency reduces vascular accumulation of apolipoprotein(a) and development of atherosclerosis in apolipoprotein(a) transgenic mice PNAS, October 13, 1998; 95(21): 12591 - 12595. [Abstract] [Full Text] [PDF]

				M. L. Rand, W. Sangrar, M. A. Hancock, D. M. Taylor, S. M. Marcovina, M. A. Packham, and M. L. Koschinsky Apolipoprotein(a) Enhances Platelet Responses to the Thrombin Receptor–Activating Peptide SFLLRN Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1393 - 1399. [Abstract] [Full Text] [PDF]

				L. B. Nielsen, K. Juul, and B. G. Nordestgaard Increased Degradation of Lipoprotein(a) in Atherosclerotic Compared With Nonlesioned Aortic Intima–Inner Media of Rabbits : In Vivo Evidence That Lipoprotein(a) May Contribute to Foam Cell Formation Arterioscler. Thromb. Vasc. Biol., April 1, 1998; 18(4): 641 - 649. [Abstract] [Full Text] [PDF]

				S. Takami, S. Yamashita, S. Kihara, M. Ishigami, K. Takemura, N. Kume, T. Kita, and Y. Matsuzawa Lipoprotein(a) Enhances the Expression of Intercellular Adhesion Molecule-1 in Cultured Human Umbilical Vein Endothelial Cells Circulation, March 3, 1998; 97(8): 721 - 728. [Abstract] [Full Text] [PDF]

				P. N. Hopkins, L. L. Wu, S. C. Hunt, B. C. James, G. M. Vincent, and R. R. Williams Lipoprotein(a) Interactions With Lipid and Nonlipid Risk Factors in Early Familial Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2783 - 2792. [Abstract] [Full Text]

				C. Kang, V. Durlach, T. Soulat, C. Fournier, and E. Angles-Cano Lipoprotein(a) Isoforms Display Differences in Affinity for Plasminogen-Like Binding to Human Mononuclear Cells Arterioscler. Thromb. Vasc. Biol., October 1, 1997; 17(10): 2036 - 2043. [Abstract] [Full Text]

				B. J. Biemond, P. W. Friederich, M. L. Koschinsky, M. Levi, W. Sangrar, J. Xia, H. R. Buller, and J. W. t. Cate Apolipoprotein(a) Attenuates Endogenous Fibrinolysis in the Rabbit Jugular Vein Thrombosis Model In Vivo Circulation, September 2, 1997; 96(5): 1612 - 1615. [Abstract] [Full Text]

				R. A. Hegele, W. C. Breckenridge, J. H. Brunt, and P. W. Connelly Genetic Variation in Factor VII Associated with Variation in Plasma Lipoprotein(a) Concentration Arterioscler. Thromb. Vasc. Biol., September 1, 1997; 17(9): 1701 - 1706. [Abstract] [Full Text]

				S. Kochl, F. Fresser, E. Lobentanz, G. Baier, and G. Utermann Novel Interaction of Apolipoprotein(a) With beta -2 Glycoprotein I Mediated by the Kringle IV Domain Blood, August 15, 1997; 90(4): 1482 - 1489. [Abstract] [Full Text] [PDF]

				Y. Yano, K. Shimokawa, Y. Okada, and A. Noma Immunolocalization of Lipoprotein(a) in Wounded Tissues J. Histochem. Cytochem., April 1, 1997; 45(4): 559 - 568. [Abstract] [Full Text] [PDF]

				B. R. Gabel, L. F. May, S. M. Marcovina, and M. L. Koschinsky Lipoprotein(a) Assembly: Quantitative Assessment of the Role of Apo(a) Kringle IV Types 2-10 in Particle Formation Arterioscler. Thromb. Vasc. Biol., December 1, 1996; 16(12): 1559 - 1567. [Abstract] [Full Text]

				S. Sunayama, H. Daida, H. Mokuno, H. Miyano, H. Yokoi, Y. J. Lee, H. Sakurai, and H. Yamaguchi Lack of Increased Coronary Atherosclerotic Risk Due to Elevated Lipoprotein(a) in Women >=55 Years of Age Circulation, September 15, 1996; 94(6): 1263 - 1268. [Abstract] [Full Text]

				K. Handa, M. Takao, J. Nomoto, K. Oku, K. Shirai, K. Saku, and K. Arakawa Evaluation of the Coagulation and Fibrinolytic Systems in Men with Intermittent Claudication Angiology, June 1, 1996; 47(6): 543 - 548. [Abstract] [PDF]

				J. L. Hoover-Plow, N. Boonmark, P. Skocir, R. Lawn, and E. F. Plow A Quantitative Immunoassay for the Lysine-Binding Function of Lipoprotein(a) : Application to Recombinant Apo(a) and Lipoprotein(a) in Plasma Arterioscler. Thromb. Vasc. Biol., May 1, 1996; 16(5): 656 - 664. [Abstract] [Full Text]

				F. Andreotti, V. Pasceri, D. R. Hackett, G. J. Davies, A. W. Haider, and A. Maseri Preinfarction Angina as a Predictor of More Rapid Coronary Thrombolysis in Patients with Acute Myocardial Infarction N. Engl. J. Med., January 4, 1996; 334(1): 7 - 12. [Abstract] [Full Text] [PDF]

				R. M. Lawn, N. W. Boonmark, K. Schwartz, G. E. Lindahl, D. P. Wade, C. D. Byrne, K. J. Fong, K. Meer, and L. Patthy The Recurring Evolution of Lipoprotein(a) J. Biol. Chem., October 13, 1995; 270(41): 24004 - 24009. [Abstract] [Full Text] [PDF]

				L. B. Nielsen, B. G. Nordestgaard, S. Stender, A. Niendorf, and K. Kjeldsen Transfer of Lipoprotein(a) and LDL Into Aortic Intima in Normal and in Cholesterol-Fed Rabbits Arterioscler. Thromb. Vasc. Biol., September 1, 1995; 15(9): 1492 - 1502. [Abstract] [Full Text]

				J. Willeit, S. Kiechl, P. Santer, F. Oberhollenzer, G. Egger, E. Jarosch, and A. Mair Lipoprotein(a) and Asymptomatic Carotid Artery Disease : Evidence of a Prominent Role in the Evolution of Advanced Carotid Plaques: The Bruneck Study Stroke, September 1, 1995; 26(9): 1582 - 1587. [Abstract] [Full Text]

				K. J. Williams and I. Tabas The Response-to-Retention Hypothesis of Early Atherogenesis Arterioscler. Thromb. Vasc. Biol., May 1, 1995; 15(5): 551 - 561. [Full Text]

				A. A.-R. Higazi, I. I. Barghouti, and R. Abu-Much Identification of an Inhibitor of Tissue-type Plasminogen Activator-mediated Fibrinolysis in Human Neutrophils J. Biol. Chem., April 21, 1995; 270(16): 9472 - 9477. [Abstract] [Full Text] [PDF]

				R. L. Desmarais, I. J. Sarembock, C. R. Ayers, S. M. Vernon, E. R. Powers, and L. W. Gimple Elevated Serum Lipoprotein(a) Is a Risk Factor for Clinical Recurrence After Coronary Balloon Angioplasty Circulation, March 1, 1995; 91(5): 1403 - 1409. [Abstract] [Full Text]

				W. Terres, E. Tatsis, B. Pfalzer, F. U. Beil, U. Beisiegel, and C. W. Hamm Rapid Angiographic Progression of Coronary Artery Disease in Patients With Elevated Lipoprotein(a) Circulation, February 15, 1995; 91(4): 948 - 950. [Abstract] [Full Text]

				P. R.J. Ames Medical Perspective Antiphospholipid Antibodies, Thrombosis and Atherosclerosis in Systemic Lupus Erythematosus: a Unifying 'Membrane Stress Syndrome' Hypothesis Lupus, October 1, 1994; 3(5): 371 - 377. [PDF]

				D. Grainger, H. Kirschenlohr, J. Metcalfe, P. Weissberg, D. Wade, and R. Lawn Proliferation of human smooth muscle cells promoted by lipoprotein(a) Science, June 11, 1993; 260(5114): 1655 - 1658. [Abstract] [PDF]