FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2234206893> ?p ?o ?g. }

• W2234206893 endingPage "757" @default.
• W2234206893 startingPage "745" @default.
• W2234206893 abstract "Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein. Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein. Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been known to be a risk factor for cardiovascular disorders, such as coronary heart disease (CHD), for 40 years (1Berg K. Dahlén G. Frick M.H. Lp(a) lipoprotein and pre-beta1-lipoprotein in patients with coronary heart disease.Clin. Genet. 1974; 6: 230-235Crossref PubMed Google Scholar, 2Dahlén G. Berg K. Gillnäs T. Ericson C. Lp(a) lipoprotein/pre-beta1-lipoprotein in Swedish middle-aged males and in patients with coronary heart disease.Clin. Genet. 1975; 7: 334-341Crossref PubMed Google Scholar). A great deal of excitement was generated when the remarkable homology between apo(a), the distinguishing protein component of Lp(a), and the fibrinolytic proenzyme, plasminogen, was discovered by protein and cDNA sequence analysis in the late 1980s (3Eaton D.L. Fless G.M. Kohr W.J. McLean J.W. Xu Q.T. Miller C.G. Lawn R.M. Scanu A.M. Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen.Proc. Natl. Acad. Sci. USA. 1987; 84: 3224-3228Crossref PubMed Scopus (342) Google Scholar, 4McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Google Scholar). It was immediately apparent that the unique structure of Lp(a) potentially constituted a molecular link between the processes of atherosclerosis (mediated by the LDL-like moiety) and thrombosis [mediated by the apo(a) moiety] that together precipitate events such as myocardial infarction (MI) and ischemic stroke. Indeed, some of the first functional studies of Lp(a) showed that it was able to compete with plasminogen for binding to endothelial cells and monocytes, a function that was mediated by apo(a) (5Miles L.A. Fless G.M. Levin E.G. Scanu A.M. Plow E.F. A potential basis for the thrombotic risks associated with lipoprotein(a).Nature. 1989; 339: 301-303Crossref PubMed Google Scholar, 6Hajjar K.A. Gavish D. Breslow J.L. Nachman R.L. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis.Nature. 1989; 339: 303-305Crossref PubMed Google Scholar). In the intervening years, a large body of data has been generated, principally through in vitro studies, that supports a procoagulant/antifibrinolytic function for apo(a), but precious little progress has been made in demonstrating that this function has pathophysiological relevance in humans. Moreover, there has been considerable disagreement about whether elevated plasma concentrations of Lp(a) are a risk factor for purely thrombotic disorders, such as venous thromboembolism, and whether these findings in any way inform our understanding of atherothrombotic events in the arterial tree. This review will delve into the mechanistic basis for the potential prothrombotic effects of Lp(a), emerging data on the effects of Lp(a) on fibrin clot structure, the latest epidemiological and genetic studies in human patients, and possible pathways forward that may bring a potential prothrombotic role of Lp(a) into greater focus. Plasminogen consists of an N-terminal tail domain, five different kringle domains, and a latent trypsin-like protease domain (Fig. 1) (7Forsgren M. Raden B. Israelsson M. Larsson K. Heden L.O. Molecular cloning and characterization of a full-length cDNA clone for human plasminogen.FEBS Lett. 1987; 213: 254-260Crossref PubMed Scopus (147) Google Scholar). Kringles are autonomously folding domains lacking any helical secondary structure and containing only a few short stretches of β-strand (8Patthy L. Trexler M. Vali Z. Banyai L. Varadi A. Kringles: modules specialized for protein binding. Homology of the gelatin-binding region of fibronectin with the kringle structures of proteases.FEBS Lett. 1984; 171: 131-136Crossref PubMed Scopus (0) Google Scholar, 9Tulinsky A. The structures of domains of blood proteins.Thromb. Haemost. 1991; 66: 16-31Crossref PubMed Scopus (38) Google Scholar). The overall kringle structure is defined as a tri-looped arrangement stabilized by the presence of three invariant disulfide bonds (8Patthy L. Trexler M. Vali Z. Banyai L. Varadi A. Kringles: modules specialized for protein binding. Homology of the gelatin-binding region of fibronectin with the kringle structures of proteases.FEBS Lett. 1984; 171: 131-136Crossref PubMed Scopus (0) Google Scholar, 9Tulinsky A. The structures of domains of blood proteins.Thromb. Haemost. 1991; 66: 16-31Crossref PubMed Scopus (38) Google Scholar). Kringles are present in several other proteases involved in coagulation and fibrinolysis, including prothrombin (two kringles), Factor XII (one kringle), tissue-type plasminogen activator (two kringles), and urokinase-type plasminogen activator (one kringle) (10Patthy L. Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules.Cell. 1985; 41: 657-663Abstract Full Text PDF PubMed Scopus (354) Google Scholar). Several other proteins also contain kringles, most notably the nonprotease hepatocyte growth factor, which contains four (11Ichinose A. Multiple members of the plasminogen-apolipoprotein(a) gene family associated with thrombosis.Biochemistry. 1992; 31: 3113-3118Crossref PubMed Scopus (0) Google Scholar). The apo(a) consists of 10 different types of kringle domains, differing in amino acid sequence, that are most homologous to plasminogen kringle IV (KIV), as well as a single plasminogen kringle V (KV)-like domain and a protease-like domain (Fig. 1) (4McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Google Scholar). Of the 10 KIV types in apo(a), 9 are present in single copy in all apo(a) isoforms (12van der Hoek Y.Y. Wittekoek M.E. Beisiegel U. Kastelein J.J. Koschinsky M.L. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.Hum. Mol. Genet. 1993; 2: 361-366Crossref PubMed Scopus (158) Google Scholar), while KIV type 2 (KIV2) is encoded in a variable number of tandemly repeated copies by the apo(a) gene (LPA), giving rise to the existence of a series of differently-sized LPA alleles and, hence, apo(a) isoforms in the human population (13Lackner C. Cohen J.C. Hobbs H.H. Molecular definition of the extreme size polymorphism in apolipoprotein(a).Hum. Mol. Genet. 1993; 2: 933-940Crossref PubMed Google Scholar). Known alleles encode as few as 1 and as many as 34 KIV2 repeats, giving rise to apo(a) isoforms containing between 10 and 43 KIV-like domains, and polypeptide molecular masses between ∼200 and ∼800 kDa (14Marcovina S.M. Albers J.J. Wijsman E. Zhang Z. Chapman N.H. Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans.J. Lipid Res. 1996; 37: 2569-2585Abstract Full Text PDF PubMed Google Scholar). The biological role of kringles is considered to be in ligand interactions (8Patthy L. Trexler M. Vali Z. Banyai L. Varadi A. Kringles: modules specialized for protein binding. Homology of the gelatin-binding region of fibronectin with the kringle structures of proteases.FEBS Lett. 1984; 171: 131-136Crossref PubMed Scopus (0) Google Scholar), often with lysine-containing substrates. Several of the kringles in plasminogen contain lysine binding sites (LBSs), defined structurally by a hydrophobic trough, lined by two or three key aromatic side chains, that binds the aliphatic backbone of the lysine side chain and that is flanked on either end by a cationic and anionic center (15Hoover G.J. Menhart N. Martin A. Warder S. Castellino F.J. Amino acids of the recombinant kringle 1 domain of human plasminogen that stabilize its interaction with omega-amino acids.Biochemistry. 1993; 32: 10936-10943Crossref PubMed Scopus (35) Google Scholar, 16McCance S.G. Menhart N. Castellino F.J. Amino acid residues of the kringle-4 and kringle-5 domains of human plasminogen that stabilize their interactions with omega-amino acid ligands.J. Biol. Chem. 1994; 269: 32405-32410Abstract Full Text PDF PubMed Google Scholar). LBSs can therefore bind to both internal lysines, as well as carboxyl-terminal lysines. Of the LBS in plasminogen, the LBS in kringle I has the highest affinity for lysine analogs, followed by KIV and KV (17Castellino F.J. McCance S.G. The kringle domains of human plasminogen.Ciba Found. Symp. 1997; 212: 46-60; discussion 60–65PubMed Google Scholar). The LBSs in plasminogen have been shown to be important for both lysine-dependent interactions with substrates, such as fibrin and cell-surface receptors (18Váli Z. Patthy L. The fibrin-binding site of human plasminogen. Arginines 32 and 34 are essential for fibrin affinity of the kringle 1 domain.J. Biol. Chem. 1984; 259: 13690-13694Abstract Full Text PDF PubMed Google Scholar, 19Wu T.P. Padmanabhan K. Tulinsky A. Mulichak A.M. The refined structure of the epsilon-aminocaproic acid complex of human plasminogen kringle 4.Biochemistry. 1991; 30: 10589-10594Crossref PubMed Google Scholar, 20Fleury V. Angles-Cano E. Characterization of the binding of plasminogen to fibrin surfaces: the role of carboxy-terminal lysines.Biochemistry. 1991; 30: 7630-7638Crossref PubMed Google Scholar), as well as for intramolecular interactions that maintain the closed native conformation of plasminogen (21Violand B.N. Byrne R. Castellino F.J. The effect of alpha-,omega-amino acids on human plasminogen structure and activation.J. Biol. Chem. 1978; 253: 5395-5401Abstract Full Text PDF PubMed Google Scholar, 22Cockell C.S. Marshall J.M. Dawson K.M. Cederholm-Williams S.A. Ponting C.P. Evidence that the conformation of unliganded human plasminogen is maintained via an intramolecular interaction between the lysine-binding site of kringle 5 and the N-terminal peptide.Biochem. J. 1998; 333: 99-105Crossref PubMed Scopus (70) Google Scholar). Of the KIV types in apo(a), only KIV5, KIV6, KIV7, KIV8, and KIV10 have LBSs, with all the other KIV types containing one or more key amino acid substitutions that inactivate their LBSs (Fig. 1) (4McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Google Scholar, 23Guevara Jr., J. Jan A.Y. Knapp R. Tulinsky A. Morrisett J.D. Comparison of ligand-binding sites of modeled apo[a] kringle-like sequences in human lipoprotein.Arterioscler. Thromb. 1993; 13 ([a]): 758-770Crossref PubMed Google Scholar). However, the LBSs in KIV5–KIV8 have been demonstrated to be of a lower affinity than the one in KIV10, due to some conservative amino acid substitutions (24Ye Q. Rahman M.N. Koschinsky M.L. Jia Z. High-resolution crystal structure of apolipoprotein(a) kringle IV type 7: insights into ligand binding.Protein Sci. 2001; 10: 1124-1129Crossref PubMed Scopus (21) Google Scholar, 25Rahman M.N. Becker L. Petrounevitch V. Hill B.C. Jia Z. Koschinsky M.L. Comparative analyses of the lysine binding site properties of apolipoprotein(a) kringle IV types 7 and 10.Biochemistry. 2002; 41: 1149-1155Crossref PubMed Scopus (13) Google Scholar). As such, the LBSs in apo(a) KIV10 and KIV5–KIV8 have been termed as “strong” and “weak” LBSs, respectively (Fig. 1), although all of these LBSs are of a lower affinity for lysine than the kringle I LBSs in plasminogen (26Marti D.N. Hu C.K. An S.S. von Haller P. Schaller J. Llinas M. Ligand preferences of kringle 2 and homologous domains of human plasminogen: canvassing weak, intermediate, and high-affinity binding sites by 1H-NMR.Biochemistry. 1997; 36: 11591-11604Crossref PubMed Scopus (56) Google Scholar). Of the lysine-binding apo(a) kringles, only KIV10 is available for interaction with lysine-containing substrates. This is because the LBSs in KIV5–KIV8 are masked when bound to apoB-100 in the Lp(a) particle (27Ernst A. Helmhold M. Brunner C. Petho-Schramm A. Armstrong V.W. Muller H.J. Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a).J. Biol. Chem. 1995; 270: 6227-6234Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 28Gabel B.R. May L.F. Marcovina S.M. Koschinsky M.L. Lipoprotein(a) assembly. Quantitative assessment of the role of apo(a) kringle IV types 2-10 in particle formation.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1559-1567Crossref PubMed Google Scholar), with KIV7–KIV8 having been explicitly shown to participate in noncovalent interactions with specific lysine residues on apoB-100 that precede covalent Lp(a) formation (29Becker L. Cook P.M. Wright T.G. Koschinsky M.L. Quantitative evaluation of the contribution of weak lysine-binding sites present within apolipoprotein(a) kringle IV types 6–8 to lipoprotein(a) assembly.J. Biol. Chem. 2004; 279: 2679-2688Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). The protease-like domain in apo(a) is catalytically inactive, despite having an intact Ser-His-Asp catalytic triad (30Gabel B.R. Koschinsky M.I. Analysis of the proteolytic activity of a recombinant form of apolipoprotein(a).Biochemistry. 1995; 34: 15777-15784Crossref PubMed Scopus (46) Google Scholar). An Arg to Ser substitution at the location analogous to the site on plasminogen that is cleaved by plasminogen activators ensures that an activating cleavage of apo(a) cannot occur (4McLean J.W. Tomlinson J.E. Kuang W.J. Eaton D.L. Chen E.Y. Fless G.M. Scanu A.M. Lawn R.M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature. 1987; 330: 132-137Crossref PubMed Google Scholar). In addition, several other amino acid substitutions relative to plasminogen, as well as a key nine-amino acid deletion in apo(a), have been proposed to render the protease-like domain in apo(a) inactive (30Gabel B.R. Koschinsky M.I. Analysis of the proteolytic activity of a recombinant form of apolipoprotein(a).Biochemistry. 1995; 34: 15777-15784Crossref PubMed Scopus (46) Google Scholar). The gene encoding apo(a) has been proposed to have arisen from duplication of the gene encoding plasminogen comparatively late in primate evolution (Fig. 1) (31Lawn R.M. Boonmark N.W. Schwartz K. Lindahl G.E. Wade D.P. Byrne C.D. Fong K.J. Meer K. Patthy L. The recurring evolution of lipoprotein(a). Insights from cloning of hedgehog apolipoprotein(a).J. Biol. Chem. 1995; 270: 24004-24009Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Indeed, Lp(a) is only present in Old World monkeys, apes, and humans. The apo(a) from all these species generally shares the isoform size heterogeneity and kringle organization observed in humans, with the exception that some species lack KV (32Tomlinson J.E. McLean J.W. Lawn R.M. Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis.J. Biol. Chem. 1989; 264: 5957-5965Abstract Full Text PDF PubMed Google Scholar, 33Hixson J.E. Britten M.L. Manis G.S. Rainwater D.L. Apolipoprotein(a) (Apo(a)) glycoprotein isoforms result from size differences in Apo(a) mRNA in baboons.J. Biol. Chem. 1989; 264: 6013-6016Abstract Full Text PDF PubMed Google Scholar, 34Doucet C. Huby T. Chapman J. Thillet J. Lipoprotein[a] in the chimpanezee: relationship of apo[a] phenotype to elevated plasma Lp[a] levels.J. Lipid Res. 1994; 35: 263-270Abstract Full Text PDF PubMed Google Scholar, 35Leibundgut G. Scipione C. Yin H. Schneider M. Boffa M.B. Green S. Yang X. Dennis E. Witztum J.L. Koschinsky M.L. et al.Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a).J. Lipid Res. 2013; 54: 2815-2830Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). What is most interesting in examining the various sequences is that independently occurring mutations have ensured that the protease-like domain is inactive and, most relevant to the role of Lp(a) in thrombosis, KIV10 is not able to bind to lysine-containing substrates in the context of Lp(a). With respect to KIV10, some species, such as chimpanzees, have a key amino acid substitution that abolishes the LBSs (34Doucet C. Huby T. Chapman J. Thillet J. Lipoprotein[a] in the chimpanezee: relationship of apo[a] phenotype to elevated plasma Lp[a] levels.J. Lipid Res. 1994; 35: 263-270Abstract Full Text PDF PubMed Google Scholar). In other species, such as baboon, the LBS is intact (in most individuals), but the lack of KV in this species prevents binding of Lp(a) to lysine-Sepharose, perhaps by promoting a conformation of apo(a) within the Lp(a) particle that masks the KIV10 LBSs (36Belczewski A.R. Ho J. Taylor Jr., F.B. Boffa M.B. Jia Z. Koschinsky M.L. Baboon lipoprotein(a) binds very weakly to lysine-agarose and fibrin despite the presence of a strong lysine-binding site in apolipoprotein(a) kringle IV type 10.Biochemistry. 2005; 44: 555-564Crossref PubMed Scopus (9) Google Scholar). Crucially, human Lp(a) can bind to lysine-Sepharose and other lysine-containing substrates, as it contains both KV and an intact LBS in KIV10, and is unique in this respect among the primates examined, except for orangutans (35Leibundgut G. Scipione C. Yin H. Schneider M. Boffa M.B. Green S. Yang X. Dennis E. Witztum J.L. Koschinsky M.L. et al.Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a).J. Lipid Res. 2013; 54: 2815-2830Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Therefore, it can be argued that human Lp(a) is uniquely pathogenic, although a correlation between Lp(a) levels and the extent of diet-induced atherosclerosis was observed in a study of rhesus and cynomolgus macaques (37Nachman R.L. Gavish D. Azrolan N. Clarkson T.B. Lipoprotein(a) in diet-induced atherosclerosis in nonhuman primates.Arterioscler. Thromb. 1991; 11: 32-38Crossref PubMed Google Scholar). The true biological role of Lp(a) is unknown, although evolution has exerted pressure to maintain an inactive protease-like domain and, less so, a lack of lysine binding. Because human Lp(a) lacks protease activity while retaining the ability to bind to lysine-containing substrates, it can readily be hypothesized that Lp(a) may interfere with the functions of plasminogen through molecular mimicry. A great many studies conducted in vitro have confirmed this concept, while offering mechanistic insights that may prove useful to test in vivo. A large body of evidence has been accumulated concerning potential pathophysiological functions of Lp(a), both proatherosclerotic and prothrombotic (Fig. 2). It is notable, however, that none of these potential mechanisms has been explicitly proved to be occurring in human patients. Moreover, because atherosclerosis and subsequent thrombosis are mechanistically interlinked, it is not clear whether the direct procoagulant/antifibrinolytic effects of Lp(a) may be at play in increasing risk for atherothrombotic events (Fig. 2). In this section and the two subsequent sections, we summarize the evidence that Lp(a) is indeed procoagulant/antifibrinolytic. The lysine-binding function of plasminogen is crucial to its fibrinolytic role. Activation of plasminogen by tissue-type plasminogen activator (tPA) does not occur at a meaningful rate in the absence of a fibrin surface, whereas lysine-dependent interactions between plasminogen and tPA with fibrin result in the formation of a ternary complex that results in efficient production of plasmin (38Hoylaerts M. Rijken D.C. Lijnen H.R. Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.J. Biol. Chem. 1982; 257: 2912-2919Abstract Full Text PDF PubMed Google Scholar). Plasminogen binding to fibrin converts the protein from a closed to an open conformation that makes it a better substrate for tPA (39Urano T. Sator de Serrano V. Gaffney P.J. Castellino F.J. Effectors of the activation of human [Glu1]plasminogen by human tissue plasminogen activator.Biochemistry. 1988; 27: 6522-6528Crossref PubMed Scopus (0) Google Scholar). Moreover, partial degradation of fibrin by plasmin results in the formation of carboxyl-terminal lysine residues that mediate positive feedback in the fibrinolytic cascade by: i) promoting plasminogen binding (40Suenson E. Petersen L.C. Fibrin and plasminogen structures essential to stimulation of plasmin formation by tissue-type plasminogen activator.Biochim. Biophys. Acta. 1986; 870: 510-519Crossref PubMed Google Scholar); ii) promoting plasmin-mediated conversion of native Glu1-plasminogen to Lys77-plasminogen, which lacks the tail domain (see Biochemistry of apo(a): Homology to Plasminogen, above) and is a better substrate for tPA (41Suenson E. Thorsen S. The course and prerequisites of Lys-plasminogen formation during fibrinolysis.Biochemistry. 1988; 27: 2435-2443Crossref PubMed Scopus (36) Google Scholar); and iii) binding to plasmin and thus protecting it from consumption by antiplasmin (42Wiman B. Collen D. Molecular mechanism of physiological fibrinolysis.Nature. 1978; 272: 549-550Crossref PubMed Google Scholar). The first studies to examine the functional implications of the homology between apo(a) and plasminogen demonstrated the ability of Lp(a) and apo(a) to inhibit binding of plasminogen to cell surface receptors on monocytes and endothelial cells (5Miles L.A. Fless G.M. Levin E.G. Scanu A.M. Plow E.F. A potential basis for the thrombotic risks associated with lipoprotein(a).Nature. 1989; 339: 301-303Crossref PubMed Google Scholar, 6Hajjar K.A. Gavish D. Breslow J.L. Nachman R.L. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis.Nature. 1989; 339: 303-305Crossref PubMed Google Scholar). The presumed competition between apo(a)/Lp(a) and plasminogen for carboxyl-terminal lysine-containing cell surface receptors, such as α-enolase and annexin AII tetramer, was speculated to inhibit cell-surface (pericellular) plasminogen activation. Direct proof of an effect of apo(a)/Lp(a) on pericellular plasminogen activation was only very recently presented by our group (43Romagnuolo R. Marcovina S.M. Boffa M.B. Koschinsky M.L. Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a).J. Lipid Res. 2014; 55: 625-634Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar); interestingly, we found that carboxyl-terminal lysines played essentially no role in the inhibition by apo(a). Inhibition of pericellular plasminogen activation by Lp(a) is probably not a large factor in thrombolysis in the context of atherothrombotic effects, as this would only generate plasmin on the periphery of the thrombus rather than on or in the thrombus. However, inhibition of pericellular plasminogen activation by apo(a) may contribute to the atherosclerotic process through persistence of mural thrombi or through effects in the vascular wall, such as extracellular matrix breakdown, cell migration, and angiogenesis (43Romagnuolo R. Marcovina S.M. Boffa M.B. Koschinsky M.L. Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a).J. Lipid Res. 2014; 55: 625-634Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Embedded in this notion is an emerging theme that we will return to in this review: the difficulty of distinguishing, in an ontological sense, the proatherosclerotic and procoagulant/antifibrinolytic effects of Lp(a). Studies performed in vitro indicate clearly that apo(a) and Lp(a) are capable of inhibiting tPA-mediated clot lysis and inhibiting tPA-mediated plasminogen activation (Fig. 3) (44Loscalzo J. Weinfeld M. Fless G.M. Scanu A.M. Lipoprotein(a), fibrin binding, and plasminogen activation.Arteriosclerosis. 1990; 10: 240-245Crossref PubMed Google Scholar, 45Edelberg J.M. Gonzalez-Gronow M. Pizzo S.V. Lipoprotein(a) inhibition of plasminogen activation by tissue-type plasminogen activator.Thromb. Res. 1990; 57: 155-162Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 46Sangrar W. Bajzar L. Nesheim M.E. Koschinsky M.L. Antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation.Biochemistry. 1995; 34: 5151-5157Crossref PubMed Google Scholar, 47Hancock M.A. Boffa M.B. Marcovina S.M. Nesheim M.E. Koschinsky M.L. 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. 2003; 278: 23260-23269Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 48Knapp J.P. Herrmann W. In vitro inhibition of fibrinolysis by apolipoprotein(a) and lipoprotein(a) is size- and concentration-dependent.Clin. Chem. Lab. Med. 2004; 42: 1013-1019Crossref PubMed Scopus (7) Google Scholar). In addition, apo(a) is able to attenuate the positive feedback step of plasmin-mediated Glu- to Lys-plasminogen conversion in the context of fibrin (Fig. 3) (49Feric N.T. Boffa M.B. Johnston S.M. Koschinsky M.L. Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation.J. Thromb. Haemost. 2008; 6: 2113-2120Crossref PubMed Scopus (38) Google Scholar). This last result is noteworthy in that it had been previously found that apo(a) was unable to inhibit fibrinolysis in a system of purified components in which the Glu- to Lys-plasminogen step was bypassed by the addition of only Lys-plasminogen (46Sangrar W. Bajzar L. Nesheim M.E. Koschinsky M.L. Antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation.Biochemistry. 1995; 34: 5151-5157Crossref PubMed Google Scholar). In addition, apo(a) was not able to influence the activity of plasmin itself in degrading fibrin (46Sangrar W. Bajzar L. Nesheim M.E. Koschinsky M.L. Antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation.Biochemistry. 1995; 34: 5151-5157Crossref PubMed Google Scholar). These findings are supported by studies of thrombolysis in rabbit jugular vein (50Biemond B.J. Friederich P.W. Koschinsky M.L. Levi M. Sangrar W. Xia J. Buller H.R. ten Cate J.W. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo.Circulation. 1997; 96: 1612-1615Crossref PubMed Google Scholar) and transgenic mice expressing apo(a) (51Palabrica T.M. Liu A.C. Aronovitz M.J. Furie B. Lawn R.M. Furie B.C. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis.Nat. Med. 1995; 1: 256-259Crossref PubMed Google Scholar). In addition, induction of carotid artery thrombosis in cynomolgus monkeys showed a relationship between Lp(a) levels in the animals and the e" @default.
• W2234206893 created "2016-06-24" @default.
• W2234206893 creator A5004439929 @default.
• W2234206893 creator A5051123834 @default.
• W2234206893 date "2016-05-01" @default.
• W2234206893 modified "2023-10-17" @default.
• W2234206893 title "Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?" @default.
• W2234206893 cites W119138727 @default.
• W2234206893 cites W1517965101 @default.
• W2234206893 cites W1519108800 @default.
• W2234206893 cites W1526544241 @default.
• W2234206893 cites W1541647944 @default.
• W2234206893 cites W1549602366 @default.
• W2234206893 cites W1579972668 @default.
• W2234206893 cites W1582296137 @default.
• W2234206893 cites W1589588612 @default.
• W2234206893 cites W1593696386 @default.
• W2234206893 cites W1604425981 @default.
• W2234206893 cites W1681995079 @default.
• W2234206893 cites W1689103194 @default.
• W2234206893 cites W1751942289 @default.
• W2234206893 cites W1785297096 @default.
• W2234206893 cites W1850301950 @default.
• W2234206893 cites W1906116337 @default.
• W2234206893 cites W1923408704 @default.
• W2234206893 cites W1961340888 @default.
• W2234206893 cites W1964403387 @default.
• W2234206893 cites W1968471163 @default.
• W2234206893 cites W1975495438 @default.
• W2234206893 cites W1976679810 @default.
• W2234206893 cites W1976854646 @default.
• W2234206893 cites W1977726586 @default.
• W2234206893 cites W1981440679 @default.
• W2234206893 cites W1986171030 @default.
• W2234206893 cites W1987256121 @default.
• W2234206893 cites W1988836289 @default.
• W2234206893 cites W1988877980 @default.
• W2234206893 cites W1990204315 @default.
• W2234206893 cites W1990224666 @default.
• W2234206893 cites W1990739538 @default.
• W2234206893 cites W1990980340 @default.
• W2234206893 cites W1991102295 @default.
• W2234206893 cites W1991445186 @default.
• W2234206893 cites W1992162856 @default.
• W2234206893 cites W1994007436 @default.
• W2234206893 cites W1994383679 @default.
• W2234206893 cites W1995592192 @default.
• W2234206893 cites W1998023491 @default.
• W2234206893 cites W2001407828 @default.
• W2234206893 cites W2001691760 @default.
• W2234206893 cites W2002146594 @default.
• W2234206893 cites W2002882735 @default.
• W2234206893 cites W2003895206 @default.
• W2234206893 cites W2005018366 @default.
• W2234206893 cites W2005117592 @default.
• W2234206893 cites W2006560848 @default.
• W2234206893 cites W2007332542 @default.
• W2234206893 cites W2007649541 @default.
• W2234206893 cites W2008170505 @default.
• W2234206893 cites W2009421935 @default.
• W2234206893 cites W2010616304 @default.
• W2234206893 cites W2010933740 @default.
• W2234206893 cites W2014729315 @default.
• W2234206893 cites W2015664419 @default.
• W2234206893 cites W2018129107 @default.
• W2234206893 cites W2027220761 @default.
• W2234206893 cites W2027664694 @default.
• W2234206893 cites W2029458605 @default.
• W2234206893 cites W2031508076 @default.
• W2234206893 cites W2031510621 @default.
• W2234206893 cites W2032242304 @default.
• W2234206893 cites W2035125534 @default.
• W2234206893 cites W2035411066 @default.
• W2234206893 cites W2036075350 @default.
• W2234206893 cites W2036170644 @default.
• W2234206893 cites W2042462913 @default.
• W2234206893 cites W2043407204 @default.
• W2234206893 cites W2043722521 @default.
• W2234206893 cites W2044967349 @default.
• W2234206893 cites W2045555091 @default.
• W2234206893 cites W2046971159 @default.
• W2234206893 cites W2048350998 @default.
• W2234206893 cites W2050927931 @default.
• W2234206893 cites W2050962788 @default.
• W2234206893 cites W2054049732 @default.
• W2234206893 cites W2057007282 @default.
• W2234206893 cites W2059930381 @default.
• W2234206893 cites W2061947823 @default.
• W2234206893 cites W2062501060 @default.
• W2234206893 cites W2066125340 @default.
• W2234206893 cites W2066991839 @default.
• W2234206893 cites W2067917588 @default.
• W2234206893 cites W2070031791 @default.
• W2234206893 cites W2071382325 @default.
• W2234206893 cites W2071717752 @default.
• W2234206893 cites W2075069959 @default.
• W2234206893 cites W2076170565 @default.
• W2234206893 cites W2076860175 @default.

• next