Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An abundant dysfunctional apolipoprotein A1 in human atheroma

Nature Medicine volume 20, pages 193–203 (2014)Cite this article

Subjects

Abstract

Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phage display affinity maturation to form a high-affinity mAb specific for apoA1 oxidized by the MPO-H2O2-halide system.
Figure 2: Epitope mapping of affinity-matured mAb r8B5.2
Figure 3: Characterization of oxTrp72-apoA1 recovered from human atherosclerotic plaque.
Figure 4: Characterization of oxTrp72-apoA1 recovered from human plasma.
Figure 5: oxTrp72-apoA1 has impaired function in vivo and is associated with CVD.
Figure 6: Formation of a dysfunctional apoA1 form, oxTrp72-apoA1, within human atherosclerotic lesions.

Similar content being viewed by others

References

  1. Barter, P.J. et al. Antiinflammatory properties of HDL. Circ. Res. 95, 764–772 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Duffy, D. & Rader, D.J. Update on strategies to increase HDL quantity and function. Nat. Rev. Cardiol. 6, 455–463 (2009).

    Article  Google Scholar 

  3. Navab, M., Reddy, S.T., Van Lenten, B.J. & Fogelman, A.M. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat. Rev. Cardiol. 8, 222–232 (2011).

    Article  CAS  Google Scholar 

  4. Khera, A.V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vickers, K.C., Palmisano, B.T., Shoucri, B.M., Shamburek, R.D. & Remaley, A.T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fisher, E.A., Feig, J.E., Hewing, B., Hazen, S.L. & Smith, J.D. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler. Thromb. Vasc. Biol. 32, 2813–2820 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gordon, T., Castelli, W.P., Hjortland, M.C., Kannel, W.B. & Dawber, T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977).

    Article  CAS  PubMed  Google Scholar 

  8. Badimon, J.J., Badimon, L., Galvez, A., Dische, R. & Fuster, V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab. Invest. 60, 455–461 (1989).

    CAS  PubMed  Google Scholar 

  9. Badimon, J.J., Badimon, L. & Fuster, V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J. Clin. Invest. 85, 1234–1241 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 353, 265–267 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Plump, A.S., Scott, C.J. & Breslow, J.L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E–deficient mouse. Proc. Natl. Acad. Sci. USA 91, 9607–9611 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Hughes, S.D., Verstuyft, J. & Rubin, E.M. HDL deficiency in genetically engineered mice requires elevated LDL to accelerate atherogenesis. Arterioscler. Thromb. Vasc. Biol. 17, 1725–1729 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Nissen, S.E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J. Am. Med. Assoc. 290, 2292–2300 (2003).

    Article  CAS  Google Scholar 

  14. Sacks, F.M. et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J. Lipid Res. 50, 894–907 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tardif, J.C. et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. J. Am. Med. Assoc. 297, 1675–1682 (2007).

    Article  Google Scholar 

  16. Barter, P.J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    Article  CAS  Google Scholar 

  17. Nissen, S.E. et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304–1316 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Boden, W.E. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Article  CAS  Google Scholar 

  19. Voight, B.F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bhattacharyya, T. et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. J. Am. Med. Assoc. 299, 1265–1276 (2008).

    Article  CAS  Google Scholar 

  21. Besler, C. et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J. Clin. Invest. 121, 2693–2708 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sorci-Thomas, M.G. & Thomas, M.J. High density lipoprotein biogenesis, cholesterol efflux, and immune cell function. Arterioscler. Thromb. Vasc. Biol. 32, 2561–2565 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shih, D.M. et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J. Biol. Chem. 275, 17527–17535 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Tang, W.H. et al. Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk. Arterioscler. Thromb. Vasc. Biol. 32, 2803–2812 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. DiDonato, J.A. et al. Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma. Circulation 128, 1644–1655 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Zheng, L. et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J. Clin. Invest. 114, 529–541 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu, Z. et al. The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction. Nat. Struct. Mol. Biol. 14, 861–868 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Peng, D.Q. et al. Apolipoprotein A-I tryptophan substitution leads to resistance to myeloperoxidase-mediated loss of function. Arterioscler. Thromb. Vasc. Biol. 28, 2063–2070 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Undurti, A. et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J. Biol. Chem. 284, 30825–30835 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hadfield, K.A. et al. Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl). Biochem. J. 449, 531–542 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Van Lenten, B.J. et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J. Clin. Invest. 96, 2758–2767 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ansell, B.J. et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108, 2751–2756 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Charles-Schoeman, C. et al. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J. Rheumatol. 34, 1459–1464 (2007).

    CAS  PubMed  Google Scholar 

  34. Shao, B., Pennathur, S. & Heinecke, J.W. Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. J. Biol. Chem. 287, 6375–6386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brennan, M.L. et al. A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase-deficient mice, and the nature of peroxidase-generated reactive nitrogen species. J. Biol. Chem. 277, 17415–17427 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Timmins, J.M. et al. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J. Clin. Invest. 115, 1333–1342 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Barter, P.J. & Kastelein, J.J. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J. Am. Coll. Cardiol. 47, 492–499 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Bergt, C. et al. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc. Natl. Acad. Sci. USA 101, 13032–13037 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Shao, B. et al. Tyrosine 192 in apolipoprotein A-I is the major site of nitration and chlorination by myeloperoxidase, but only chlorination markedly impairs ABCA1-dependent cholesterol transport. J. Biol. Chem. 280, 5983–5993 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Cybulsky, M.I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Segrest, J.P. et al. A detailed molecular belt model for apolipoprotein A-I in discoidal high density lipoprotein. J. Biol. Chem. 274, 31755–31758 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Wu, Z. et al. Double superhelix model of high density lipoprotein. J. Biol. Chem. 284, 36605–36619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gogonea, V. et al. Congruency between biophysical data from multiple platforms and molecular dynamics simulation of the double-super helix model of nascent high-density lipoprotein. Biochemistry 49, 7323–7343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu, Z. et al. The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering. J. Biol. Chem. 286, 12495–12508 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gogonea, V. et al. The low-resolution structure of nHDL reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion. J. Lipid Res. 54, 966–983 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pattison, D.I. & Davies, M.J. Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds. Chem. Res. Toxicol. 14, 1453–1464 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Baldus, S. et al. Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. J. Clin. Invest. 108, 1759–1770 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Abu-Soud, H.M. & Hazen, S.L. Nitric oxide is a physiological substrate for mammalian peroxidases. J. Biol. Chem. 275, 37524–37532 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Eiserich, J.P. et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296, 2391–2394 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, Y. et al. Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation. J. Biol. Chem. 282, 31826–31834 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sugiyama, S. et al. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler. Thromb. Vasc. Biol. 24, 1309–1314 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Nahrendorf, M. et al. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117, 1153–1160 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ronald, J.A. et al. Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 120, 592–599 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hazen, S.L. & Heinecke, J.W. 3-chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J. Clin. Invest. 99, 2075–2081 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zamanian-Daryoush, M. et al. The cardioprotective protein apolipoprotein A1 promotes potent anti-tumorigenic effects. J. Biol. Chem. 288, 21237–21252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Markwell, M.A., Haas, S.M., Bieber, L.L. & Tolbert, N.E. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal. Biochem. 87, 206–210 (1978).

    Article  CAS  PubMed  Google Scholar 

  57. Ryan, R.O., Forte, T.M. & Oda, M.N. Optimized bacterial expression of human apolipoprotein A-I. Protein Expr. Purif. 27, 98–103 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Matz, C.E. & Jonas, A. Micellar complexes of human apolipoprotein A-I with phosphatidylcholines and cholesterol prepared from cholate-lipid dispersions. J. Biol. Chem. 257, 4535–4540 (1982).

    CAS  PubMed  Google Scholar 

  59. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  Google Scholar 

  60. Todorovski, T., Fedorova, M., Hennig, L. & Hoffmann, R. Synthesis of peptides containing 5-hydroxytryptophan, oxindolylalanine, N-formylkynurenine and kynurenine. J. Pept. Sci. 17, 256–262 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Ståhlman, M. et al. Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose or in KBr. J. Lipid Res. 49, 481–490 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Robinet, P., Wang, Z., Hazen, S.L. & Smith, J.D. A simple and sensitive enzymatic method for cholesterol quantification in macrophages and foam cells. J. Lipid Res. 51, 3364–3369 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Barbas, C.F. III, Burton, D.R., Scott, J.K. & Silverman, G.J. Phage Display: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001).

  64. Marks, J.D. et al. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222, 581–597 (1991).

    Article  CAS  PubMed  Google Scholar 

  65. Chung, S. et al. Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism. J. Biol. Chem. 285, 12197–12209 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Liang (Chinese Center for Disease Control and Prevention) for the gift of the dicistronic baculoviral shuttle vector used to subclone the scFv gene. This study was supported by US National Institutes of Health (NIH) grants P01HL098055 and HL119962. BioBank, the clinical study from which samples were analyzed, was supported in part from NIH grants P01HL098055, P01HL076491, R01HL103866, P20HL113452 and R01HL103931. This work was also supported in part by a grant from the LeDucq Fondation. S.L.H. is also partially supported by a gift from the Leonard Krieger Fund. Mass spectrometry instrumentation used was housed within the Cleveland Clinic Mass Spectrometry Facility, which is partially supported through a Center of Innovation Award by AB SCIEX.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

    Ying Huang, Joseph A DiDonato, Bruce S Levison, Dave Schmitt, Lin Li, Jennifer Buffa, Timothy Kim, Gary S Gerstenecker, Xiaodong Gu, Chandra S Kadiyala, Zeneng Wang, Miranda K Culley, Jennie E Hazen, Anthony J DiDonato, Xiaoming Fu, Stela Z Berisha, Daoquan Peng, Truc T Nguyen, Leslie Cho, Paul L Fox, Valentin Gogonea, W H Wilson Tang, Jonathan D Smith & Stanley L Hazen

  2. Department of Mathematics, Cleveland State University, Cleveland, Ohio, USA

    Yuping Wu

  3. Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA

    Gary S Gerstenecker & Valentin Gogonea

  4. Cleveland Heart Lab, Cleveland, Ohio, USA

    Shaohong Liang

  5. Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, USA, North Carolina

    Chia-Chi Chuang & John S Parks

  6. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

    Leslie Cho, Edward F Plow, W H Wilson Tang, Jonathan D Smith & Stanley L Hazen

  7. Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA

    Edward F Plow

  8. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

    John S Parks

  9. Department of Cardiovascular Medicine, New York University School of Medicine, New York, New York, USA

    Edward A Fisher

Authors
  1. Ying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph A DiDonato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce S Levison
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dave Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuping Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jennifer Buffa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Timothy Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gary S Gerstenecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaodong Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chandra S Kadiyala
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zeneng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Miranda K Culley
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jennie E Hazen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Anthony J DiDonato
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xiaoming Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stela Z Berisha
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Daoquan Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Truc T Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Shaohong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Chia-Chi Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Leslie Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Edward F Plow
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Paul L Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Valentin Gogonea
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. W H Wilson Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. John S Parks
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Edward A Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Jonathan D Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Stanley L Hazen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.H. participated in all laboratory, animal and human studies, assisted in statistical analyses, helped design the experiments and drafted the manuscript. B.S.L., G.S.G., V.G., C.S.K., Z.W. and X.F. assisted with various laboratory and mass spectrometry studies. D.S., J.B., M.K.C., S.Z.B. and C.-C.C. helped perform various animal experiments. J.A.D., D.S., T.K., X.G., M.K.C., J.E.H., A.J.D. and D.P. helped make various bacterial expression clones and produce and purify recombinant proteins used. J.A.D. and S.L. helped with mAb generation and screening. T.K. and T.T.N. helped with ELISA assays. L.L. and Y.W. provided statistical analyses of clinical data. J.A.D., L.C., E.F.P., P.L.F., V.G., W.H.W.T., J.S.P., E.A.F., J.D.S. and S.L.H. provided experimental analysis and expertise. All authors took part in critical review of the manuscript. The project was scientifically conceived and directed by S.L.H.

Corresponding author

Correspondence to Stanley L Hazen.

Ethics declarations

Competing interests

W.H.W.T. has previously received research grant support from Abbott Laboratories. S.L.H., Z.W., B.S.L. and J.D.S. report being listed as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. S.L.H. reports having been paid as a consultant for the following companies: AstraZeneca Pharmaceuticals LP, Cleveland Heart Lab, Esperion, Lilly, Liposcience Inc., Merck & Co., Inc., Pfizer Inc., Procter & Gamble and Takeda. S.L.H. reports receiving research funds from Cleveland Heart Lab, Liposcience Inc., Procter & Gamble and Takeda. J.D.S. reports having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab and Esperion and being paid as a consultant for Esperion. S.L.H. reports having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from the following companies: Cleveland Heart Lab, Esperion, Frantz Biomarkers, LLC and Liposcience Inc. B.S.L. and Z.W. report having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics from Liposcience Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–2, Supplementary Figures 1–8 (PDF 2429 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, Y., DiDonato, J., Levison, B. et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 20, 193–203 (2014). https://doi.org/10.1038/nm.3459

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3459

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing