Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Feb 1;97(3):858–864. doi: 10.1172/JCI118487

Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a).

V Mooser 1, M C Seabra 1, M Abedin 1, K T Landschulz 1, S Marcovina 1, H H Hobbs 1
PMCID: PMC507126  PMID: 8609245

Abstract

Apo(a) is a large glycoprotein of unknown function that circulates in plasma as part of lipoprotein(a). Apo(a) is structurally related to plasminogen and contains at least 10 kringle (K)4 repeats (type 1-10), a K5 repeat and sequences similar to the protease domain of plasminogen. Plasminogen generates two biologically active peptides: plasmin and angiostatin, a kringle-containing peptide. As a first step in determining if apo(a) generates a similar kringle-containing peptide, human urine was immunologically examined. Fragments ranging in size from 85 to 215 kD were immunodetected using antibodies directed against epitopes in the K4-type 2 repeat, but not the K4-type 9 repeat or protease domain, NH2-terminal sequence analysis revealed sequences specific for the K4-type 1 repeat, confirming that the fragments are from the NH2 terminus of the K4 array. The amount of urinary apo(a) rose in proportion to the plasma lipoprotein(a) concentration. Even individuals with trace to no apo(a) in plasma had immunodetectable apo(a) fragments in their urine. Intravenous administration of the human urinary apo(a) into mice resulted in the urine. These findings suggest that the apo(a) fragments found in urine are formed extrarenally and then excreted by the kidney.

Full Text

The Full Text of this article is available as a PDF (328.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albers J. J., Marcovina S. M., Lodge M. S. The unique lipoprotein(a): properties and immunochemical measurement. Clin Chem. 1990 Dec;36(12):2019–2026. [PubMed] [Google Scholar]
  2. Azrolan N., Gavish D., Breslow J. L. Plasma lipoprotein(a) concentration is controlled by apolipoprotein(a) (apo(a)) protein size and the abundance of hepatic apo(a) mRNA in a cynomolgus monkey model. J Biol Chem. 1991 Jul 25;266(21):13866–13872. [PubMed] [Google Scholar]
  3. Byrne C. D., Schwartz K., Lawn R. M. Loss of a splice donor site at a 'skipped exon' in a gene homologous to apolipoprotein(a) leads to an mRNA encoding a protein consisting of a single kringle domain. Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):65–70. doi: 10.1161/01.atv.15.1.65. [DOI] [PubMed] [Google Scholar]
  4. Chiesa G., Hobbs H. H., Koschinsky M. L., Lawn R. M., Maika S. D., Hammer R. E. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a). J Biol Chem. 1992 Dec 5;267(34):24369–24374. [PubMed] [Google Scholar]
  5. Curtiss L. K., Edgington T. S. Immunochemical heterogeneity of human plasma apolipoprotein B. I. Apolipoprotein B binding of mouse hybridoma antibodies. J Biol Chem. 1982 Dec 25;257(24):15213–15221. [PubMed] [Google Scholar]
  6. Cushing G. L., Gaubatz J. W., Nava M. L., Burdick B. J., Bocan T. M., Guyton J. R., Weilbaecher D., DeBakey M. E., Lawrie G. M., Morrisett J. D. Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis. 1989 Sep-Oct;9(5):593–603. doi: 10.1161/01.atv.9.5.593. [DOI] [PubMed] [Google Scholar]
  7. Dieplinger H., Gruber G., Krasznai K., Reschauer S., Seidel C., Burns G., Müller H. J., Császár A., Vogel W., Robenek H. Kringle 4 of human apolipoprotein[a] shares a linear antigenic site with human catalase. J Lipid Res. 1995 Apr;36(4):813–822. [PubMed] [Google Scholar]
  8. Fless G. M., ZumMallen M. E., Scanu A. M. Physicochemical properties of apolipoprotein(a) and lipoprotein(a-) derived from the dissociation of human plasma lipoprotein (a). J Biol Chem. 1986 Jul 5;261(19):8712–8718. [PubMed] [Google Scholar]
  9. Gaw A., Boerwinkle E., Cohen J. C., Hobbs H. H. Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common "null" allele at the apo(a) locus. J Clin Invest. 1994 Jun;93(6):2526–2534. doi: 10.1172/JCI117263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gaw A., Hobbs H. H. Molecular genetics of lipoprotein (a): new pieces to the puzzle. Curr Opin Lipidol. 1994 Apr;5(2):149–155. doi: 10.1097/00041433-199404000-00012. [DOI] [PubMed] [Google Scholar]
  11. Hartmann G., Naldini L., Weidner K. M., Sachs M., Vigna E., Comoglio P. M., Birchmeier W. A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11574–11578. doi: 10.1073/pnas.89.23.11574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hoff H. F., O'Neil J., Smejkal G. B., Yashiro A. Immunochemically detectable lipid-free apo(a) in plasma and in human atherosclerotic lesions. Chem Phys Lipids. 1994 Jan;67-68:271–280. doi: 10.1016/0009-3084(94)90147-3. [DOI] [PubMed] [Google Scholar]
  13. Huby T., Doucet C., Dieplinger H., Chapman J., Thillet J. Structural domains of apolipoprotein(a) and its interaction with apolipoprotein B-100 in the lipoprotein(a) particle. Biochemistry. 1994 Mar 22;33(11):3335–3341. doi: 10.1021/bi00177a026. [DOI] [PubMed] [Google Scholar]
  14. Itakura Y., Yamamoto T., Matsumoto K., Nakamura T. Autocrine stimulation of motility in SBC-5 human lung carcinoma cells by a two-kringle variant of HGF. Cancer Lett. 1994 Aug 15;83(1-2):235–243. doi: 10.1016/0304-3835(94)90325-5. [DOI] [PubMed] [Google Scholar]
  15. Jokinen E. V., Landschulz K. T., Wyne K. L., Ho Y. K., Frykman P. K., Hobbs H. H. Regulation of the very low density lipoprotein receptor by thyroid hormone in rat skeletal muscle. J Biol Chem. 1994 Oct 21;269(42):26411–26418. [PubMed] [Google Scholar]
  16. Knight B. L. Lp(a) catabolism in hypercholesterolaemic individuals. Chem Phys Lipids. 1994 Jan;67-68:233–239. doi: 10.1016/0009-3084(94)90142-2. [DOI] [PubMed] [Google Scholar]
  17. Knight B. L., Perombelon Y. F., Soutar A. K., Wade D. P., Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects. Atherosclerosis. 1991 Apr;87(2-3):227–237. doi: 10.1016/0021-9150(91)90025-x. [DOI] [PubMed] [Google Scholar]
  18. Koschinsky M. L., Beisiegel U., Henne-Bruns D., Eaton D. L., Lawn R. M. Apolipoprotein(a) size heterogeneity is related to variable number of repeat sequences in its mRNA. Biochemistry. 1990 Jan 23;29(3):640–644. doi: 10.1021/bi00455a007. [DOI] [PubMed] [Google Scholar]
  19. Lackner C., Cohen J. C., Hobbs H. H. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet. 1993 Jul;2(7):933–940. doi: 10.1093/hmg/2.7.933. [DOI] [PubMed] [Google Scholar]
  20. Laplaud P. M., Beaubatie L., Rall S. C., Jr, Luc G., Saboureau M. Lipoprotein[a] is the major apoB-containing lipoprotein in the plasma of a hibernator, the hedgehog (Erinaceus europaeus). J Lipid Res. 1988 Sep;29(9):1157–1170. [PubMed] [Google Scholar]
  21. Lawn R. M. Lipoprotein(a) in heart disease. Sci Am. 1992 Jun;266(6):54–60. doi: 10.1038/scientificamerican0692-54. [DOI] [PubMed] [Google Scholar]
  22. Magnaghi P., Citterio E., Malgaretti N., Acquati F., Ottolenghi S., Taramelli R. Molecular characterisation of the human apo(a)-plasminogen gene family clustered on the telomeric region of chromosome 6 (6q26-27). Hum Mol Genet. 1994 Mar;3(3):437–442. doi: 10.1093/hmg/3.3.437. [DOI] [PubMed] [Google Scholar]
  23. Makino K., Abe A., Maeda S., Noma A., Kawade M., Takenaka O. Lipoprotein(a) in nonhuman primates. Presence and characteristics of Lp(a) immunoreactive materials using anti-human Lp(a) serum. Atherosclerosis. 1989 Jul;78(1):81–85. doi: 10.1016/0021-9150(89)90161-5. [DOI] [PubMed] [Google Scholar]
  24. Marcovina S. M., Albers J. J., Gabel B., Koschinsky M. L., Gaur V. P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995 Feb;41(2):246–255. [PubMed] [Google Scholar]
  25. McLean 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 Nov 12;330(6144):132–137. doi: 10.1038/330132a0. [DOI] [PubMed] [Google Scholar]
  26. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  27. Oida K., Takai H., Maeda H., Takahashi S., Shimada A., Suzuki J., Tamai T., Nakai T., Miyabo S. Apolipoprotein(a) is present in urine and its excretion is decreased in patients with renal failure. Clin Chem. 1992 Nov;38(11):2244–2248. [PubMed] [Google Scholar]
  28. Phillips M. L., Lembertas A. V., Schumaker V. N., Lawn R. M., Shire S. J., Zioncheck T. F. Physical properties of recombinant apolipoprotein(a) and its association with LDL to form an LP(a)-like complex. Biochemistry. 1993 Apr 13;32(14):3722–3728. doi: 10.1021/bi00065a026. [DOI] [PubMed] [Google Scholar]
  29. Rader D. J., Mann W. A., Cain W., Kraft H. G., Usher D., Zech L. A., Hoeg J. M., Davignon J., Lupien P., Grossman M. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest. 1995 Mar;95(3):1403–1408. doi: 10.1172/JCI117794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rath M., Niendorf A., Reblin T., Dietel M., Krebber H. J., Beisiegel U. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis. 1989 Sep-Oct;9(5):579–592. doi: 10.1161/01.atv.9.5.579. [DOI] [PubMed] [Google Scholar]
  31. Reblin T., Meyer N., Labeur C., Henne-Bruns D., Beisiegel U. Extraction of lipoprotein(a), apo B, and apo E from fresh human arterial wall and atherosclerotic plaques. Atherosclerosis. 1995 Mar;113(2):179–188. doi: 10.1016/0021-9150(94)05445-o. [DOI] [PubMed] [Google Scholar]
  32. Sarkar G., Cassady J., Bottema C. D., Sommer S. S. Characterization of polymerase chain reaction amplification of specific alleles. Anal Biochem. 1990 Apr;186(1):64–68. doi: 10.1016/0003-2697(90)90573-r. [DOI] [PubMed] [Google Scholar]
  33. Seman L. J., Jenner J. L., McNamara J. R., Schaefer E. J. Quantification of lipoprotein(a) in plasma by assaying cholesterol in lectin-bound plasma fraction. Clin Chem. 1994 Mar;40(3):400–403. [PubMed] [Google Scholar]
  34. Tomlinson J. E., McLean J. W., Lawn R. M. Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis. J Biol Chem. 1989 Apr 5;264(10):5957–5965. [PubMed] [Google Scholar]
  35. Wade D. P., Knight B. L., Harders-Spengel K., Soutar A. K. Detection and quantitation of apolipoprotein(a) mRNA in human liver and its relationship with plasma lipoprotein(a) concentration. Atherosclerosis. 1991 Nov;91(1-2):63–72. doi: 10.1016/0021-9150(91)90187-8. [DOI] [PubMed] [Google Scholar]
  36. White A. L., Rainwater D. L., Lanford R. E. Intracellular maturation of apolipoprotein[a] and assembly of lipoprotein[a] in primary baboon hepatocytes. J Lipid Res. 1993 Mar;34(3):509–517. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES