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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Aug;87(16):6204–6207. doi: 10.1073/pnas.87.16.6204

Hypothesis: lipoprotein(a) is a surrogate for ascorbate.

M Rath 1, L Pauling 1
PMCID: PMC54501  PMID: 2143582

Abstract

The concept that lipoprotein(a) [Lp(a)] is a surrogate for ascorbate is suggested by the fact that this lipoprotein is found generally in the blood of primates and the guinea pig, which have lost the ability to synthesize ascorbate, but only rarely in the blood of other animals. Properties of Lp(a) that are shared with ascorbate, in accordance with this hypothesis, are the acceleration of wound healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation. High plasma Lp(a) is associated with coronary heart disease and other forms of atherosclerosis in humans, and the incidence of cardiovascular disease is decreased by elevated ascorbate. Similar observations have been made in cancer and diabetes. We have formulated the hypothesis that Lp(a) is a surrogate for ascorbate in humans and other species and have marshaled the evidence bearing on this hypothesis.

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Selected References

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

  1. Ames B. N., Cathcart R., Schwiers E., Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858–6862. doi: 10.1073/pnas.78.11.6858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armstrong V. W., Cremer P., Eberle E., Manke A., Schulze F., Wieland H., Kreuzer H., Seidel D. The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis. Dependence on serum LDL levels. Atherosclerosis. 1986 Dec;62(3):249–257. doi: 10.1016/0021-9150(86)90099-7. [DOI] [PubMed] [Google Scholar]
  3. BERG K. A NEW SERUM TYPE SYSTEM IN MAN--THE LP SYSTEM. Acta Pathol Microbiol Scand. 1963;59:369–382. doi: 10.1111/j.1699-0463.1963.tb01808.x. [DOI] [PubMed] [Google Scholar]
  4. BLUMBERG B. S., BERNANKE D., ALLISON A. C. A human lipoprotein polymorphism. J Clin Invest. 1962 Oct;41:1936–1944. doi: 10.1172/JCI104651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bihari-Varga M., Gruber E., Rotheneder M., Zechner R., Kostner G. M. Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta. Arteriosclerosis. 1988 Nov-Dec;8(6):851–857. doi: 10.1161/01.atv.8.6.851. [DOI] [PubMed] [Google Scholar]
  6. Brown M. S., Goldstein J. L. Plasma lipoproteins: teaching old dogmas new tricks. Nature. 1987 Nov 12;330(6144):113–114. doi: 10.1038/330113a0. [DOI] [PubMed] [Google Scholar]
  7. Bruckert E., Davidoff P., Grimaldi A., Truffert J., Giral P., Doumith R., Thervet F., De Gennes J. L. Increased serum levels of lipoprotein(a) in diabetes mellitus and their reduction with glycemic control. JAMA. 1990 Jan 5;263(1):35–36. [PubMed] [Google Scholar]
  8. Cameron E. Biological function of ascorbic acid and the pathogenesis of scurvy: a working hypothesis. Med Hypotheses. 1976 Jul-Aug;2(4):154–163. doi: 10.1016/0306-9877(76)90072-4. [DOI] [PubMed] [Google Scholar]
  9. Cameron E., Pauling L., Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. 1979 Mar;39(3):663–681. [PubMed] [Google Scholar]
  10. 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]
  11. Eaton 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 U S A. 1987 May;84(10):3224–3228. doi: 10.1073/pnas.84.10.3224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Enstrom J. E., Pauling L. Mortality among health-conscious elderly Californians. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6023–6027. doi: 10.1073/pnas.79.19.6023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frei B., England L., Ames B. N. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6377–6381. doi: 10.1073/pnas.86.16.6377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ginter E., Babala J., Cerven J. The effect of chronic hypovitaminosis C on the metabolism of cholesterol and atherogenisis in guinea pigs. J Atheroscler Res. 1969 Nov-Dec;10(3):341–352. doi: 10.1016/s0368-1319(69)80037-2. [DOI] [PubMed] [Google Scholar]
  15. Gonzalez-Gronow M., Edelberg J. M., Pizzo S. V. Further characterization of the cellular plasminogen binding site: evidence that plasminogen 2 and lipoprotein a compete for the same site. Biochemistry. 1989 Mar 21;28(6):2374–2377. doi: 10.1021/bi00432a005. [DOI] [PubMed] [Google Scholar]
  16. Hajjar 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 May 25;339(6222):303–305. doi: 10.1038/339303a0. [DOI] [PubMed] [Google Scholar]
  17. Harpel P. C., Gordon B. R., Parker T. S. Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin. Proc Natl Acad Sci U S A. 1989 May;86(10):3847–3851. doi: 10.1073/pnas.86.10.3847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hoff H. F., Beck G. J., Skibinski C. I., Jürgens G., O'Neil J., Kramer J., Lytle B. Serum Lp(a) level as a predictor of vein graft stenosis after coronary artery bypass surgery in patients. Circulation. 1988 Jun;77(6):1238–1244. doi: 10.1161/01.cir.77.6.1238. [DOI] [PubMed] [Google Scholar]
  19. Hume R., Weyers E., Rowan T., Reid D. S., Hillis W. S. Leucocyte ascorbic acid levels after acute myocardial infarction. Br Heart J. 1972 Mar;34(3):238–243. doi: 10.1136/hrt.34.3.238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Karàdi I., Kostner G. M., Gries A., Nimpf J., Romics L., Malle E. Lipoprotein (a) and plasminogen are immunochemically related. Biochim Biophys Acta. 1988 May 2;960(1):91–97. doi: 10.1016/0005-2760(88)90013-6. [DOI] [PubMed] [Google Scholar]
  21. Knox E. G. Ischaemic-heart-disease mortality and dietary intake of calcium. Lancet. 1973 Jun 30;1(7818):1465–1467. doi: 10.1016/s0140-6736(73)91808-4. [DOI] [PubMed] [Google Scholar]
  22. Kunert K. J., Tappel A. L. The effect of vitamin C on in vivo lipid peroxidation in guinea pigs as measured by pentane and ethane production. Lipids. 1983 Apr;18(4):271–274. doi: 10.1007/BF02534701. [DOI] [PubMed] [Google Scholar]
  23. Költringer P., Jürgens G. A dominant role of lipoprotein(a) in the investigation and evaluation of parameters indicating the development of cervical atherosclerosis. Atherosclerosis. 1985 Dec;58(1-3):187–198. doi: 10.1016/0021-9150(85)90065-6. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Maeda S., Abe A., Seishima M., Makino K., Noma A., Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis. 1989 Aug;78(2-3):145–150. doi: 10.1016/0021-9150(89)90218-9. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Miles 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 May 25;339(6222):301–303. doi: 10.1038/339301a0. [DOI] [PubMed] [Google Scholar]
  28. Nambisan B., Kurup P. A. Ascorbic acid and glycosaminoglycan and lipid metabolism in guinea pigs fed normal and atherogenic diets. Atherosclerosis. 1975 Nov-Dec;22(3):447–461. doi: 10.1016/0021-9150(75)90024-6. [DOI] [PubMed] [Google Scholar]
  29. Niendorf A., Rath M., Wolf K., Peters S., Arps H., Beisiegel U., Dietel M. Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries. Virchows Arch A Pathol Anat Histopathol. 1990;417(2):105–111. doi: 10.1007/BF02190527. [DOI] [PubMed] [Google Scholar]
  30. Nishikimi M., Udenfriend S. Immunologic evidence that the gene for L-gulono-gamma-lactone oxidase is not expressed in animals subject to scurvy. Proc Natl Acad Sci U S A. 1976 Jun;73(6):2066–2068. doi: 10.1073/pnas.73.6.2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Salonen E. M., Jauhiainen M., Zardi L., Vaheri A., Ehnholm C. Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it. EMBO J. 1989 Dec 20;8(13):4035–4040. doi: 10.1002/j.1460-2075.1989.tb08586.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Som S., Basu S., Mukherjee D., Deb S., Choudhury P. R., Mukherjee S., Chatterjee S. N., Chatterjee I. B. Ascorbic acid metabolism in diabetes mellitus. Metabolism. 1981 Jun;30(6):572–577. doi: 10.1016/0026-0495(81)90133-5. [DOI] [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. Utermann G., Hoppichler F., Dieplinger H., Seed M., Thompson G., Boerwinkle E. Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4171–4174. doi: 10.1073/pnas.86.11.4171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Utermann G., Kraft H. G., Menzel H. J., Hopferwieser T., Seitz C. Genetics of the quantitative Lp(a) lipoprotein trait. I. Relation of LP(a) glycoprotein phenotypes to Lp(a) lipoprotein concentrations in plasma. Hum Genet. 1988 Jan;78(1):41–46. doi: 10.1007/BF00291232. [DOI] [PubMed] [Google Scholar]
  37. WILLIS G. C., FISHMAN S. Ascorbic acid content of human arterial tissue. Can Med Assoc J. 1955 Apr 1;72(7):500–503. [PMC free article] [PubMed] [Google Scholar]
  38. WILLIS G. C., LIGHT A. W., GOW W. S. Serial arteriography in atherosclerosis. Can Med Assoc J. 1954 Dec;71(6):562–568. [PMC free article] [PubMed] [Google Scholar]
  39. WILLIS G. C. The reversibility of atherosclerosis. Can Med Assoc J. 1957 Jul 15;77(2):106–108. [PMC free article] [PubMed] [Google Scholar]
  40. Wright L. C., Sullivan D. R., Muller M., Dyne M., Tattersall M. H., Mountford C. E. Elevated apolipoprotein(a) levels in cancer patients. Int J Cancer. 1989 Feb 15;43(2):241–244. doi: 10.1002/ijc.2910430212. [DOI] [PubMed] [Google Scholar]

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