Impact of Apolipoprotein(a) Isoform Size Heterogeneity on the Lysine Binding Function of Lipoprotein(a) in Early Onset Coronary Artery Disease

Summary

Elevated plasma Lp(a) is an independent risk factor for cardiovascular disease. Unique to Lp(a) is the apoprotein, apo(a) which can vary from 250 to 800 kDa in molecular weight. Small isoforms are also associated with the risk of cardiovascular disease. The purpose of this study was to examine the association of Lp(a) concentration, apo(a) size, and Lp(a) lysine-binding site(s) (LBS) function in patients with early onset heart disease, and age-matched controls. Mean values of Lp(a) were significantly higher in the patients than for the age-matched group. The smallest molecular weight isoform for each subject had significantly fewer kringles for the patients than the age-matched controls. There was a significant correlation between LBS activity and kringle number in the single-banded phenotypes of the patients, but not the controls. LBS activity was significantly higher in patients with small isoforms (≤18 kringles) compared to controls. The odds ratio for coronary artery disease for high LBS activity and high Lp(a) concentration was 4.4 (p = 0.002) and for high LBS activity and small isoforms was 10.1 (p = 0.002). In the patients, Lp(a) concentration was higher, apo(a) size was smaller, and LBS activity higher in the small isoforms compared to the controls. This study suggests an association of high LBS activity in small isoforms of Lp(a) with disease in humans.

Keywords

Lipoprotein(a) - apo(a) size - lysine binding site function - myocardial infarction

^* Reprint requests to: Dr. Jorge Joven at Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Calle Sant Joan s/n, 43201, Reus, Spain – Tel.: [phone]; Fax: [phone]; e-mail: [e-mail]

• References

• 1 Kronenberg F, Steinmetz A, Kostner GM, Dieplinger H. Lipoprotein(a) in health and disease. Crit Rev Clin Lab Sci 1996; 33: 495-543.
• 2 Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993; 270: 2195-9.
• 3 Scanu AM, Edelstein C. Kringle-dependent structural and functional polymorphism of apolipoprotein(a). Biochim Biophys Acta 1995; 1256: 1-12.
• 4 McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-7.
• 5 Lackner C, Boerwinkle E, Leffert CC, Rahmig T, Hobbs HH. Molecular basis of apolipoprotein(a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest 1991; 87: 2153-61.
• 6 Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp(a) glycoprotein phenotypes: Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 1987; 80: 458-65.
• 7 Wu T-P, Padmanabhan K, Tulinsky A, Mulichak AM. The refined structure of the ε-aminocaproic acid complex of human plasminogen kringle 4. Biochemistry 1991; 30: 10589-94.
• 8 Ernst A, Helmhold M, Brunner C, Pethö-Schramm A, Armstrong VW, Müller 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: 6227-34.
• 9 Rouy D, Koschinsky ML, Fleury V, Chapman J, Anglés-Cano E. Apolipoprotein(a) and plasminogen interactions with fibrin: A study with recombinant apolipoprotein(a) and isolated plasminogen fragments. Biochemistry 1992; 31: 6333-9.
• 10 Klezovitch O, Edelstein C, Scanu AM. Evidence that the fibrinogen binding domain of Apo(a) is outside the lysine bidning site of kringle IV-10: A study involving naturally occurring lysine binding defective lipoprotein(a) phenotypes. J Clin Invest 1996; 98: 185-91.
• 11 Miles LA, Fless GM, Scanu AM, Baynham P, Sebald MT, Skocir P, Curtiss LK, Levin EG, Hoover-Plow JL, Plow EF. Interaction of Lp(a) with plasminogen binding sites on cells. Thromb Haemost 1995; 73: 458-65.
• 12 Miles LA, Sebald MT, Fless GM, Scanu AM, Curtiss LK, Plow EF, Hoover-Plow JL. Interaction of lipoprotein(a) with the extracellular matrix. Fibrinolysis Proteolysis 1998; 12: 79-87.
• 13 Boonmark NW, Lou XJ, Yang ZJ, Schwartz K, Zhang JL, Rubin EM, Lawn RM. Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice. J Clin Invest 1997; 100: 558-64.
• 14 Hoover-Plow JL, Boonmark N, Skocir P, Lawn R, Plow EF. A quantitative immunoassay for the lysine-binding function of lipoprotein(a): Application to recombinant apo(a) and lipoprotein(a) in plasma, and modified lipoprotein(a). Arterioscler Thromb Vasc Biol 1996; 16: 656-64.
• 15 Scanu AM, Pfaffinger D, Lee JC, Hinman J. A single point mutation (Trp72 Arg) in human apo(a) kringle 4-37 associated with a lysine binding defect in Lp(a). Biochim Biophys Acta 1994; 1227: 41-5.
• 16 Scanu AM, Miles LA, Pfaffinger D, Fless GM, Jackson E, Hoover-Plow JL, Brunck T, Plow EF. Rhesus monkey Lp(a) binds to lysine-Sepharose and U937 monocytoid cells less efficiently than human Lp(a). Evidence for a dominant role of kringle 437. J Clin Invest 1993; 91: 283-91.
• 17 Kang C, Durlach V, Soulat T, Fournier C, Anglés-Cano E. Lipoprotein(a) isoforms display differences in affinity for plasminogen-like binding to human mononuclear cells. Arterioscler Thromb Vasc Biol 1997; 17: 2036-43.
• 18 Hoover-Plow J, Skocir P. Enzymatic and chemical modifications of lipoprotein(a) selectively alter its lysine-binding functions. Biochim Biophys Acta Lipids Lipid Metab 1998; 1392: 73-84.
• 19 Joven J, Simó JM, Vilella E, Camps J, Masana L, De Febrer G, Camprubí M, Richart C, Bardaji A, Casao E, Pocovi M, Civeira F. Lipoprotein(a) and the significance of the association between platelet glycoprotein IIIa polymorphisms and the risk of premature myocardial infarction. Atherosclerosis 1998; 140: 155-9.
• 20 Simó JM, Castellano I, Ferré N, Joven J, Camps J. Evaluation of a homogeneous assay for high density lipoprotein cholesterol: Limitations in patients with cardiovascular, renal and hepatic disorders. Clin Chem 1998; 44: 1233-41.
• 21 Levine DM, Sloan BJ, Donner JE, Lorenz JD, Heinzerling RH. Automated measurement of lipoprotein(a) by immunoturbidimetric analysis. Int J. Clin Lab Res 1992; 22: 173-8.
• 22 Gaubatz JW, Ghanem KI, Guevara J, Nava ML, Patsch W, Morrisett JD. Polymorphic forms of human apolipoprotein(a): Inheritance and relationship of their molecular weights to plasma levels of lipoprotein(a). J Lipid Res 1990; 31: 603-13.
• 23 Martin S, Ladona MG, Pedro-Botet J, Covas MI, Rubies-Prat J. Differential expression of double-band apolipoprotein(a) phenotypes in healthy Spanish subjects detected by SDS-agarose immunoblotting. Clin Chim Acta 1998; 277: 191-205.
• 24 Hoover-Plow JL, Miles LA, Fless GM, Scanu AM, Plow EF. Comparison of the lysine binding functions of lipoprotein(a) and plasminogen. Biochemistry 1993; 32: 13681-7.
• 25 Kraft HG, Sandholzer C, Menzel HJ, Utermann G. Apolipoprotein(a) alleles determine lipoprotein(a) particle density and concentration in plasma. Arterioscler Thromb 1992; 12: 302-6.
• 26 Lindén T, Taddei-Peters W, Wilhelmsen L, Herlitz J, Karlsson T, Ullström C, Wiklund O. Serum lipids, lipoprotein(a) and apo(a) isoforms in patients with established coronary artery disease and their relation to disease and prognosis after coronary bypass surgery. Atherosclerosis 1998; 137: 175-86.
• 27 Klausen IC, Sjol A, Hansen PS, Gerdes LU, Moller L, Lemming L, Schroll M, Faergeman O. Apolipoprotein(a) isoforms and coronary heart disease in men – A nested case-control study. Atherosclerosis 1997; 132: 77-84.
• 28 Gazzaruso C, Geroldi D, Garzaniti A, Falcone C, Frantino P, Finardi G, Buscaglia P. Apolipoprotein(a) phenotypes as genetic markers of coronary atherosclerosis severity. Int J. Cardiol 1998; 64: 277-84.
• 29 Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res 1996; 37: 2569-85.
• 30 Rotimi CN, Cooper RS, Marcovina SM, McGee D, Owoaje E, Ladipo M. Serum distribution of lipoprotein(a) in African Americans and Nigerians: Potential evidence for a genotype-environmental effect. Genet Epidemiol 1997; 14: 157-68.
• 31 Srinivasan SR, Dahlén GH, Jarpa RA, Webber LS, Berenson GS. Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children: Bogalusa Heart Study. Circulation 1991; 84: 160-7.
• 32 Hughes SD, Lou XJ, Ighani S, Verstuyft J, Grainger DJ, Lawn RM, Rubin EM. Lipoprotein(a) vascular accumulation in mice – In vivo analysis of the role of lysine binding sites using recombinant adenovirus. J Clin Invest 1997; 100: 1493-500.
• 33 Karmansky I, Shnaider H, Palant A, Gruener N. Lysine-binding species of lipoprotein(a) in coronary artery disease. Eur J. Clin Invest 1994; 24: 360-6.
• 34 Hoover-Plow J, Khaitan A, Fless GM. Phospholipase A2 modification enhances lipoprotein(a) binding to the subendothelial matrix. Thromb Haemost 1998; 79: 640-8.
• 35 Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis – Prospective results from the Bruneck study. Circulation 1999; 100: 1154-60.
• 36 Hervio L, Girard-globa A, Durlach V, Angles-Cano E. The antifibrinolytic effect of lipoprotein(a) in heterozygous subjects is modulated by the relative concentration of each of the apolipoprotein(a) isoforms and their affinity for fibrin. Eur J. Clin Invest 1996; 26: 411-7.
• 37 Hervio L, Chapman M, Thillet J, Loyau S, Anglés-Cano E. Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?. Blood 1993; 82: 392-7.
• 38 Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J. Clin. Invest. 1992; 90: 52-60.
• 39 Gazzaruso C, Garzaniti A, Buscaglia P, Bonetti G, Falcone C, Fratino P, Finardi G, Geroldi D. Association betrween apolipoprotein(a) phenotypes and coronary heart disease at a young age. J Am Coll Cardiol 1999; 33: 157-63.
• 40 Geroldi D, Bellotti V, Buscaglia P, Bonetti G, Gazzaruso C, Caprioli A, Fratino P. Characterization of apo(a) polymorphism by a modified immunoblotting technique in an Italian population sample. Clinica Chimica Acta 1993; 221: 159-69.
• 41 Rainwater DL, Ludwig MJ, Haffner SM, VandeBerg JL. Lipid and lipo-protein factors associated with variation in Lp(a) density. Arterioscler Thromb Vasc Biol 1995; 15: 313-9.
• 42 Valenti K, Aveynier E, Laporte F, Hadjian AJ. Evaluation of the genoty-ping and phenotypind approaches in the investigation of apolipoprotein(a) size polymorphism. Clin Chim Acta 1997; 263: 249-60.
• 43 Prins J, Van der Hoek YY, Biesheuvel TH, Leus FR, van Rijn HJM, Kastelein JJP. The func tional and clinical significance of the Met Thr substitution in kringle IV type 10 of apolipoprotein(a). Thromb. Res. 1998; 90: 125-130.
• 44 Xue S, Green MA, LoGrasso PV, Boettcher BR, Madison EL, Curtiss LK, Miles LA. Comparison of the effects of Apo(a) kringle IV-10 and plasminogen kringles on the interactions of lipoprotein(a) with regulatory molecules. Thromb Haemost 1999; 81: 428-35.