Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 15;100(2):464–474. doi: 10.1172/JCI119554

Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles.

L W Castellani 1, M Navab 1, B J Van Lenten 1, C C Hedrick 1, S Y Hama 1, A M Goto 1, A M Fogelman 1, A J Lusis 1
PMCID: PMC508211  PMID: 9218525

Abstract

Previous studies showed that transgenic mice overexpressing either apolipoprotein AI (apoAI) or apolipoprotein AII (apoAII), the major proteins of HDL, exhibited elevated levels of HDL cholesterol, but, whereas the apoAI-transgenic mice were protected against atherosclerosis, the apoAII-transgenic mice had increased lesion development. We now examine the basis for this striking functional heterogeneity. HDL from apoAI transgenics exhibited an enhanced ability to promote cholesterol efflux from macrophages, but HDL from apoAII transgenics and nontransgenics were not discernibly different in efflux studies. In contrast with HDL from nontransgenics and apoAI transgenics, HDL from the apoAII transgenics were unable to protect against LDL oxidation in a coculture model of the artery wall. Furthermore, HDL taken from apoAII-transgenic mice, but not HDL taken from either the apoAI transgenics or nontransgenic littermate controls, by itself stimulated lipid hydroperoxide formation in artery wall cells and induced monocyte transmigration, indicating that the apoAII-transgenic HDL were in fact proinflammatory. This loss in the ability of the apoAII-transgenic HDL to function as an antioxidant/antiinflammatory agent was associated with a decreased content of paraoxonase, an enzyme that protects against LDL oxidation. Reconstitution of the apoAII transgenic HDL with purified paraoxonase restored both paraoxonase activity and the ability to protect against LDL oxidation. We conclude that overexpression of apoAII converts HDL from an anti- to a proinflammatory particle and that paraoxonase plays a role in this transformation.

Full Text

The Full Text of this article is available as a PDF (264.6 KB).

Selected References

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

  1. Auerbach B. J., Kiely J. S., Cornicelli J. A. A spectrophotometric microtiter-based assay for the detection of hydroperoxy derivatives of linoleic acid. Anal Biochem. 1992 Mar;201(2):375–380. doi: 10.1016/0003-2697(92)90354-a. [DOI] [PubMed] [Google Scholar]
  2. Barbaras R., Puchois P., Fruchart J. C., Ailhaud G. Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem Biophys Res Commun. 1987 Jan 15;142(1):63–69. doi: 10.1016/0006-291x(87)90451-7. [DOI] [PubMed] [Google Scholar]
  3. Baumberger C., Ulevitch R. J., Dayer J. M. Modulation of endotoxic activity of lipopolysaccharide by high-density lipoprotein. Pathobiology. 1991;59(6):378–383. doi: 10.1159/000163681. [DOI] [PubMed] [Google Scholar]
  4. Berliner J. A., Navab M., Fogelman A. M., Frank J. S., Demer L. L., Edwards P. A., Watson A. D., Lusis A. J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488–2496. doi: 10.1161/01.cir.91.9.2488. [DOI] [PubMed] [Google Scholar]
  5. Bernard D. W., Rodriguez A., Rothblat G. H., Glick J. M. Influence of high density lipoprotein on esterified cholesterol stores in macrophages and hepatoma cells. Arteriosclerosis. 1990 Jan-Feb;10(1):135–144. doi: 10.1161/01.atv.10.1.135. [DOI] [PubMed] [Google Scholar]
  6. Blatter Garin M. C., Abbott C., Messmer S., Mackness M., Durrington P., Pometta D., James R. W. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations. Biochem J. 1994 Dec 1;304(Pt 2):549–554. doi: 10.1042/bj3040549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blatter M. C., James R. W., Messmer S., Barja F., Pometta D. Identification of a distinct human high-density lipoprotein subspecies defined by a lipoprotein-associated protein, K-45. Identity of K-45 with paraoxonase. Eur J Biochem. 1993 Feb 1;211(3):871–879. doi: 10.1111/j.1432-1033.1993.tb17620.x. [DOI] [PubMed] [Google Scholar]
  8. Bowry V. W., Stanley K. K., Stocker R. High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10316–10320. doi: 10.1073/pnas.89.21.10316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eggesbø J. B., Hjermann I., Lund P. K., Joø G. B., Ovstebø R., Kierulf P. LPS-induced release of IL-1 beta, IL-6, IL-8, TNF-alpha and sCD14 in whole blood and PBMC from persons with high or low levels of HDL-lipoprotein. Cytokine. 1994 Sep;6(5):521–529. doi: 10.1016/1043-4666(94)90080-9. [DOI] [PubMed] [Google Scholar]
  10. Fielding C. J., Fielding P. E. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995 Feb;36(2):211–228. [PubMed] [Google Scholar]
  11. Flegel W. A., Baumstark M. W., Weinstock C., Berg A., Northoff H. Prevention of endotoxin-induced monokine release by human low- and high-density lipoproteins and by apolipoprotein A-I. Infect Immun. 1993 Dec;61(12):5140–5146. doi: 10.1128/iai.61.12.5140-5146.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fogelman A. M., Elahi F., Sykes K., Van Lenten B. J., Territo M. C., Berliner J. A. Modification of the Recalde method for the isolation of human monocytes. J Lipid Res. 1988 Sep;29(9):1243–1247. [PubMed] [Google Scholar]
  13. Gan K. N., Smolen A., Eckerson H. W., La Du B. N. Purification of human serum paraoxonase/arylesterase. Evidence for one esterase catalyzing both activities. Drug Metab Dispos. 1991 Jan-Feb;19(1):100–106. [PubMed] [Google Scholar]
  14. Hegele R. A., Brunt J. H., Connelly P. W. A polymorphism of the paraoxonase gene associated with variation in plasma lipoproteins in a genetic isolate. Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):89–95. doi: 10.1161/01.atv.15.1.89. [DOI] [PubMed] [Google Scholar]
  15. Hegele R. A., Brunt J. H., Connelly P. W. Multiple genetic determinants of variation of plasma lipoproteins in Alberta Hutterites. Arterioscler Thromb Vasc Biol. 1995 Jul;15(7):861–871. doi: 10.1161/01.atv.15.7.861. [DOI] [PubMed] [Google Scholar]
  16. Johnson W. J., Kilsdonk E. P., van Tol A., Phillips M. C., Rothblat G. H. Cholesterol efflux from cells to immunopurified subfractions of human high density lipoprotein: LP-AI and LP-AI/AII. J Lipid Res. 1991 Dec;32(12):1993–2000. [PubMed] [Google Scholar]
  17. Kawano M., Miida T., Fielding C. J., Fielding P. E. Quantitation of pre beta-HDL-dependent and nonspecific components of the total efflux of cellular cholesterol and phospholipid. Biochemistry. 1993 May 18;32(19):5025–5028. doi: 10.1021/bi00070a008. [DOI] [PubMed] [Google Scholar]
  18. Lorentz K., Flatter B., Augustin E. Arylesterase in serum: elaboration and clinical application of a fixed-incubation method. Clin Chem. 1979 Oct;25(10):1714–1720. [PubMed] [Google Scholar]
  19. Mackness M. I., Arrol S., Abbott C., Durrington P. N. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993 Dec;104(1-2):129–135. doi: 10.1016/0021-9150(93)90183-u. [DOI] [PubMed] [Google Scholar]
  20. Mackness M. I., Arrol S., Durrington P. N. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 1991 Jul 29;286(1-2):152–154. doi: 10.1016/0014-5793(91)80962-3. [DOI] [PubMed] [Google Scholar]
  21. Mackness M. I., Harty D., Bhatnagar D., Winocour P. H., Arrol S., Ishola M., Durrington P. N. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991 Feb;86(2-3):193–199. doi: 10.1016/0021-9150(91)90215-o. [DOI] [PubMed] [Google Scholar]
  22. McElveen J., Mackness M. I., Colley C. M., Peard T., Warner S., Walker C. H. Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. Clin Chem. 1986 Apr;32(4):671–673. [PubMed] [Google Scholar]
  23. Miller N. E. Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J. 1987 Feb;113(2 Pt 2):589–597. doi: 10.1016/0002-8703(87)90638-7. [DOI] [PubMed] [Google Scholar]
  24. Navab M., Hough G. P., Stevenson L. W., Drinkwater D. C., Laks H., Fogelman A. M. Monocyte migration into the subendothelial space of a coculture of adult human aortic endothelial and smooth muscle cells. J Clin Invest. 1988 Dec;82(6):1853–1863. doi: 10.1172/JCI113802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Navab M., Imes S. S., Hama S. Y., Hough G. P., Ross L. A., Bork R. W., Valente A. J., Berliner J. A., Drinkwater D. C., Laks H. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 1991 Dec;88(6):2039–2046. doi: 10.1172/JCI115532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ohta T., Nakamura R., Ikeda Y., Shinohara M., Miyazaki A., Horiuchi S., Matsuda I. Differential effect of subspecies of lipoprotein containing apolipoprotein A-I on cholesterol efflux from cholesterol-loaded macrophages: functional correlation with lecithin: cholesterol acyltransferase. Biochim Biophys Acta. 1992 Nov 11;1165(1):119–128. doi: 10.1016/0005-2760(92)90083-8. [DOI] [PubMed] [Google Scholar]
  27. Oikawa S., Mendez A. J., Oram J. F., Bierman E. L., Cheung M. C. Effects of high-density lipoprotein particles containing apo A-I, with or without apo A-II, on intracellular cholesterol efflux. Biochim Biophys Acta. 1993 Jan 10;1165(3):327–334. doi: 10.1016/0005-2760(93)90144-x. [DOI] [PubMed] [Google Scholar]
  28. Parthasarathy S., Barnett J., Fong L. G. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta. 1990 May 22;1044(2):275–283. doi: 10.1016/0005-2760(90)90314-n. [DOI] [PubMed] [Google Scholar]
  29. Parthasarathy S., Santanam N. Mechanisms of oxidation, antioxidants, and atherosclerosis. Curr Opin Lipidol. 1994 Oct;5(5):371–375. doi: 10.1097/00041433-199410000-00009. [DOI] [PubMed] [Google Scholar]
  30. Parthasarathy S., Steinberg D., Witztum J. L. The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis. Annu Rev Med. 1992;43:219–225. doi: 10.1146/annurev.me.43.020192.001251. [DOI] [PubMed] [Google Scholar]
  31. Pavković E., Simeon V., Reiner E., Sućić M., Lipovac V. Serum paraoxonase and cholinesterase activities in individuals with lipid and glucose metabolism disorders. Chem Biol Interact. 1993 Jun;87(1-3):179–182. doi: 10.1016/0009-2797(93)90040-6. [DOI] [PubMed] [Google Scholar]
  32. Pieters M. N., Castro G. R., Schouten D., Duchateau P., Fruchart J. C., Van Berkel T. J. Cholesterol esters selectively delivered in vivo by high-density-lipoprotein subclass LpA-I to rat liver are processed faster into bile acids than are LpA-I/A-II-derived cholesterol esters. Biochem J. 1993 Jun 15;292(Pt 3):819–823. doi: 10.1042/bj2920819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Qiao J. H., Xie P. Z., Fishbein M. C., Kreuzer J., Drake T. A., Demer L. L., Lusis A. J. Pathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification. Arterioscler Thromb. 1994 Sep;14(9):1480–1497. doi: 10.1161/01.atv.14.9.1480. [DOI] [PubMed] [Google Scholar]
  34. Rader D. J., Ikewaki K., Duverger N., Feuerstein I., Zech L., Connor W., Brewer H. B., Jr Very low high-density lipoproteins without coronary atherosclerosis. Lancet. 1993 Dec 11;342(8885):1455–1458. doi: 10.1016/0140-6736(93)92933-k. [DOI] [PubMed] [Google Scholar]
  35. Rubin E. M., Krauss R. M., Spangler E. A., Verstuyft J. G., Clift S. M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991 Sep 19;353(6341):265–267. doi: 10.1038/353265a0. [DOI] [PubMed] [Google Scholar]
  36. Saha N., Roy A. C., Teo S. H., Tay J. S., Ratnam S. S. Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins. Clin Genet. 1991 Oct;40(4):277–282. doi: 10.1111/j.1399-0004.1991.tb03096.x. [DOI] [PubMed] [Google Scholar]
  37. Schultz J. R., Verstuyft J. G., Gong E. L., Nichols A. V., Rubin E. M. Protein composition determines the anti-atherogenic properties of HDL in transgenic mice. Nature. 1993 Oct 21;365(6448):762–764. doi: 10.1038/365762a0. [DOI] [PubMed] [Google Scholar]
  38. Shih D. M., Gu L., Hama S., Xia Y. R., Navab M., Fogelman A. M., Lusis A. J. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest. 1996 Apr 1;97(7):1630–1639. doi: 10.1172/JCI118589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stafforini D. M., McIntyre T. M., Prescott S. M. Platelet-activating factor acetylhydrolase from human plasma. Methods Enzymol. 1990;187:344–357. doi: 10.1016/0076-6879(90)87041-z. [DOI] [PubMed] [Google Scholar]
  40. Stafforini D. M., Zimmerman G. A., McIntyre T. M., Prescott S. M. The platelet-activating factor acetylhydrolase from human plasma prevents oxidative modification of low-density lipoprotein. Trans Assoc Am Physicians. 1992;105:44–63. [PubMed] [Google Scholar]
  41. Tall A. R. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. 1990 Aug;86(2):379–384. doi: 10.1172/JCI114722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Vosbeck K., Tobias P., Mueller H., Allen R. A., Arfors K. E., Ulevitch R. J., Sklar L. A. Priming of polymorphonuclear granulocytes by lipopolysaccharides and its complexes with lipopolysaccharide binding protein and high density lipoprotein. J Leukoc Biol. 1990 Feb;47(2):97–104. doi: 10.1002/jlb.47.2.97. [DOI] [PubMed] [Google Scholar]
  43. Walsh A., Ito Y., Breslow J. L. High levels of human apolipoprotein A-I in transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL3. J Biol Chem. 1989 Apr 15;264(11):6488–6494. [PubMed] [Google Scholar]
  44. Warden C. H., Hedrick C. C., Qiao J. H., Castellani L. W., Lusis A. J. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science. 1993 Jul 23;261(5120):469–472. doi: 10.1126/science.8332912. [DOI] [PubMed] [Google Scholar]
  45. Watson A. D., Berliner J. A., Hama S. Y., La Du B. N., Faull K. F., Fogelman A. M., Navab M. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Dec;96(6):2882–2891. doi: 10.1172/JCI118359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Watson A. D., Navab M., Hama S. Y., Sevanian A., Prescott S. M., Stafforini D. M., McIntyre T. M., Du B. N., Fogelman A. M., Berliner J. A. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Feb;95(2):774–782. doi: 10.1172/JCI117726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wurfel M. M., Kunitake S. T., Lichenstein H., Kane J. P., Wright S. D. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994 Sep 1;180(3):1025–1035. doi: 10.1084/jem.180.3.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. von Hodenberg E., Heinen S., Howell K. E., Luley C., Kübler W., Bond H. M. Cholesterol efflux from macrophages mediated by high-density lipoprotein subfractions, which differ principally in apolipoprotein A-I and apolipoprotein A-II ratios. Biochim Biophys Acta. 1991 Nov 5;1086(2):173–184. doi: 10.1016/0005-2760(91)90005-3. [DOI] [PubMed] [Google Scholar]

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

RESOURCES