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HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms

Abstract

The lipoprotein HDL has two important roles: first, it promotes reverse cholesterol transport, and second, it modulates inflammation. Epidemiological studies show that HDL-cholesterol levels are inversely correlated with the risk of cardiovascular events. However, many patients who experience a clinical event have normal, or even high, levels of HDL cholesterol. Measuring HDL-cholesterol levels provides information about the size of the HDL pool, but does not predict HDL composition or function. The main component of HDL, apolipoprotein A-I (apo A-I), is largely responsible for reverse cholesterol transport through the macrophage ATP-binding cassette transporter ABCA1. Apo A-I can be damaged by oxidative mechanisms, which render the protein less able to promote cholesterol efflux. HDL also contains a number of other proteins that are affected by the oxidative environment of the acute-phase response. Modification of the protein components of HDL can convert it from an anti-inflammatory to a proinflammatory particle. Small peptides that mimic some of the properties of apo A-I have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDL-cholesterol levels. Robust assays to evaluate the function of HDL are needed to supplement the measurement of HDL-cholesterol levels in the clinic.

Key Points

  • HDL-cholesterol levels are inversely correlated with the risk of clinical events resulting from atherosclerosis, although many patients who experience cardiovascular events have normal, or even high, levels of HDL cholesterol

  • HDL-cholesterol levels provide a measure of the size of the HDL pool, but do not predict the composition or function of HDL

  • A major function of HDL is to promote cholesterol efflux and reverse cholesterol transport, which are mediated by interaction with the macrophage ATP-binding cassette transporters ABCA1 and ABCG1

  • The main protein component of HDL, apolipoprotein A-I, can be damaged by oxidative mechanisms that render it less able to promote cholesterol efflux

  • HDL contains several other proteins that are affected by the oxidative environment of the acute-phase response, causing HDL to change from an anti-inflammatory particle to a proinflammatory particle

  • Peptides that mimic the lipid-binding properties of apolipoprotein A-I have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDL-cholesterol levels

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Figure 1: Functions and properties of HDL.
Figure 2: Lipid biosynthesis, storage, and elimination.
Figure 3: Anti-inflammatory properties of HDL.

References

  1. 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 

  2. Lewington, S. et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370, 1829–1839 (2007).

    Article  PubMed  CAS  Google Scholar 

  3. Di Angelantonio, E. et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Briel, M. et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 338, b92 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. van der Steeg, W. A. et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk. The IDEAL and EPIC-Norfolk studies. J. Am. Coll. Cardiol. 51, 634–642 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Lund-Katz, S. & Phillips, M. C. High density lipoprotein structure-function and role in reverse cholesterol transport. Subcell. Biochem. 51, 183–227 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vedhachalam, C. et al. Influence of apolipoprotein (Apo) A-I structure on nascent high density lipoprotein (HDL) particle size distribution. J. Biol. Chem. 285, 31965–31973 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Eisenberg, S. High density lipoprotein metabolism. J. Lipid Res. 25, 1017–1058 (1984).

    Article  CAS  PubMed  Google Scholar 

  10. Fagerholm, U. Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation. J. Pharm. Pharmacol. 60, 535–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Praseetha, S. & Thampan, R. V. Regulatory factors in steroid hormone biosynthesis. Crit. Rev. Eukaryot. Gene Expr. 19, 253–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Simons, K. & Gerl, M. J. Revitalizing membrane rafts: new tools and insights. Nat. Rev. Mol. Cell Biol. 11, 688–699 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Steck, T. L. & Lange, Y. Cell cholesterol homeostasis: mediation by active cholesterol. Trends Cell Biol. 20, 680–687 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Levitan, I., Volkov, S. & Subbaiah, P. V. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid. Redox Signal. 13, 39–75 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Baldán, A., Bojanic, D. D. & Edwards, P. A. The ABCs of sterol transport. J. Lipid Res. 50, S80–S85 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Yvan-Charvet, L., Wang, N. & Tall, A. R. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler. Thromb. Vasc. Biol. 30, 139–143 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Out, R. et al. Coexistence of foam cells and hypocholesterolemia in mice lacking the ABC transporters A1 and G1. Circ. Res. 102, 113–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. de la Llera-Moya, M. et al. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 796–801 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chau, P., Nakamura, Y., Fielding, C. J. & Fielding, P. E. Mechanism of prebeta-HDL formation and activation. Biochemistry 45, 3981–3987 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Jones, M. K., Catte, A., Li, L. & Segrest, J. P. Dynamics of activation of lecithin:cholesterol acyltransferase by apolipoprotein A-I. Biochemistry 48, 11196–11210 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. 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  Google Scholar 

  23. Yvan-Charvet, L. et al. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ. Res. 106, 1861–1869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Westerterp, M. et al. Increased atherosclerosis in mice with vascular ATP-binding cassette transporter G1 deficiency—brief report. Arteroscler. Thromb. Vasc. Biol. 30, 2103–2105 (2010).

    Article  CAS  Google Scholar 

  25. Masson, D. et al. Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor. Arterioscler. Thromb. Vasc. Biol. 29, 2054–2060 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, X. et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J. Clin. Invest. 117, 2216–2224 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rader, D. J., Alexander, E. T., Weibel, G. L., Billheimer, J. & Rothblat, G. H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J. Lipid Res. 50, S189–S194 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sethi, A. A. et al. High pre-β1 HDL concentrations and low lecithin:cholesterol acyltransferase activities are strong positive risk markers for ischemic heart disease and independent of HDL-cholesterol. Clin. Chem. 56, 1128–1137 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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 

  30. Zheng, L. et al. Localization of nitration and chlorination sites of apolipoprotein A-I catalyzed by myeloperoxidase in human atheroma and associated oxidative impairment in ABCA1-dependent cholesterol efflux from macrophages. J. Biol. Chem. 280, 38–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. 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  PubMed Central  Google Scholar 

  32. Shao, B. et al. Myeloperoxidase impairs ABCA1-dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I. J. Biol. Chem. 281, 9001–9004 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Shao, B., Cavigiolio, G., Brot, N., Oda, M. N. & Heinecke, J. W. Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I. Proc. Natl Acad. Sci. USA 105, 12224–12229 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shao, B., Tang, C., Heinecke, J. & Oram, J. F. Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export. J. Lipid Res. 51, 1849–1858 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Proudfoot, J. M. et al. HDL is the major lipoprotein carrier of plasma F2-isoprostanes. J. Lipid Res. 50, 716–722 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shao, B. & Heinecke, J. W. HDL, lipid peroxidation, and atherosclerosis. J. Lipid Res. 50, 599–601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cavigiolio, G., Geier, E. G., Shao, B., Heinecke, J. W. & Oda, M. N. Exchange of apolipoprotein A-I between lipid-associated and lipid-free states: a potential target for oxidative generation of dysfunctional high density lipoproteins. J. Biol. Chem. 285, 18847–18857 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fogelman, A. M. et al. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc. Natl Acad. Sci. USA 77, 2214–2218 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shao, B. et al. Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway. J. Biol. Chem. 285, 18473–18484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Steinberg, D. The cholesterol controversy is over. Why did it take so long? Circulation 80, 1070–1078 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Cohen, J. C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Gomaraschi, M. et al. Normal vascular function despite low levels of high-density lipoprotein cholesterol in carriers of the apolipoprotein A-IMilano mutant. Circulation 116, 2165–2172 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Ibanez, B. et al. Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-IMilano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis. J. Am. Coll. Cardiol. 51, 1104–1109 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Alexander, E. T. et al. Macrophage reverse cholesterol transport in mice expressing apoA-I Milano. Arterioscler. Thromb. Vasc. Biol. 29, 1496–1501 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Inazu, A. et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N. Engl. J. Med. 323, 1234–1238 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Edmondson, A. C. et al. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J. Clin. Invest. 119, 1042–1050 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Khera, A. V., Wolfe, M. L., Cannon, C. P., Qin, J. & Rader, D. J. On-statin cholesteryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study). Am. J. Cardiol. 106, 451–456 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Castrillo, A. et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell 12, 805–816 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Braun, A. et al. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ. Res. 90, 270–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Van Eck, M. et al. Increased oxidative stress in scavenger receptor BI knockout mice with dysfunctional HDL. Arterioscler. Thromb. Vasc. Biol. 27, 2413–2419 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Navab, M. et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J. Lipid Res. 41, 1495–1508 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Kontush, A. & Chapman, M. J. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr. Opin. Lipidol. 21, 312–318 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Rye, K. A., Bursill, C. A., Lambert, G., Tabet, F. & Barter, P. J. The metabolism and anti-atherogenic properties of HDL. J. Lipid Res. 50, S195–S200 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Navab, M. et al. 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. 88, 2039–2046 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Navab, M. et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1. J. Lipid Res. 41, 1481–1494 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Corsetti, J. P., Zareba, W., Moss, A. J., Rainwater, D. L. & Sparks, C. E. Elevated HDL is a risk factor for recurrent coronary events in a subgroup of non-diabetic postinfarction patients with hypercholesterolemia and inflammation. Atherosclerosis 187, 191–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Corsetti, J. P., Gansevoort, R. T., Sparks, C. E. & Dullaart, R. P. Inflammation reduces HDL protection against primary cardiac risk. Eur. J. Clin. Invest. 40, 483–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Corsetti, J. P. et al. Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels. Arterioscler. Thromb. Vasc. Biol. 30, 1657–1664 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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 

  62. McGillicuddy, F. C. et al. Inflammation impairs reverse cholesterol transport in vivo. Circulation 119, 1135–1145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Watanabe, J. et al. Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein. J. Biol. Chem. 284, 18292–18301 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Van Lenten, B. J. et al. High-density lipoprotein loses its anti-inflammatory properties during acute influenza A infection. Circulation 103, 2283–2288 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Navab, M. et al. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J. Clin. Invest. 99, 2005–2019 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Navab, M. et al. A cell-free assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating oxidized phospholipids. J. Lipid Res. 42, 1308–1317 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Dullaart, R. P. et al. Plasma lecithin:cholesterol acyltransferase activity modifies the inverse relationship of C-reactive protein with HDL cholesterol in nondiabetic men. Biochim. Biohphys. Acta 1801, 84–88 (2010).

    Article  CAS  Google Scholar 

  68. Patel, S. et al. Acute hypertriglyceridaemia in humans increases the triglyceride content and decreases the anti-inflammatory capacity of high density lipoproteins. Atherosclerosis 204, 424–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Vaisar, T. et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J. Clin. Invest. 117, 746–756 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoofnagle, A. N. & Heinecke, J. W. Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structure, and function of lipoproteins. J. Lipid Res. 50, 1967–1975 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Spagnuolo, M. S., Cigliano, L., D'Andrea, L. D., Pedone, C. & Abrescia, P. Assignment of the binding site for haptoglobin on apolipoprotein A-I. J. Biol. Chem. 280, 1193–1198 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Watanabe, J. et al. Differential association of hemoglobin with proinflammatory high density lipoproteins in atherogenic/hyperlipidemic mice. A novel biomarker of atherosclerosis. J. Biol. Chem. 282, 23698–23707 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Asleh, R. et al. Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2–2 genotype. Diabetes 57, 2794–2800 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Levy, A. P. et al. Haptoglobin: basic and clinical aspects. Antioxid. Redox Signal. 12, 293–304 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Asleh, R. & Levy, A. P. Divergent effects of α-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and Hp 2–2 genotype. Antioxid. Redox Signal. 12, 209–217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mackness, B. & Mackness, M. Anti-inflammatory properties of paraoxonase-1 in atherosclerosis. Adv. Exp. Med. Biol. 660, 143–151 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. James, R. W. et al. The scavenger receptor class B, type I is a primary determinant of paraoxonase-1 association with high-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 30, 2121–2127 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Navab, M. et al. Oral D-4F causes formation of pre-β high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 109, 3215–3220 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Imaizumi, S. et al. L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL in mice. Drug Metab. Lett. 4, 139–148 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Morgantini, C. et al. ApoA-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a mouse model of diabetes. Diabetes 59, 3223–3228 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yan, D., Navab, M., Bruce, C., Fogelman, A. M. & Jiang, X. C. PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity. J. Lipid Res. 45, 1852–1858 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Moerland, M. et al. Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice. J. Lipid Res. 48, 2622–2631 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Bloedon, L. T. et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J. Lipid Res. 49, 1344–1352 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Vaziri, N. D., Moradi, H., Pahl, M. V., Fogelman, A. M. & Navab, M. In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-I mimetic peptide. Kidney Int. 76, 437–444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Navab, M. et al. The double jeopardy of HDL. Ann. Med. 37, 173–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Van Lenten, B. J. et al. Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits. J. Lipid Res. 48, 2344–2353 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Kalantar-Zadeh, K., Kopple, J. D., Kamranpour, N., Fogelman, A. M. & Navab, M. HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int. 72, 1149–1156 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Dodani, S. et al. Can dysfunctional HDL explain high coronary artery disease risk in South Asians? Int. J. Cardiol. 129, 125–132 (2008).

    Article  PubMed  Google Scholar 

  90. McMahon, M. et al. Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheum. 60, 2428–2437 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Skaggs, B. J., Hahn, B. H., Sahakian, L., Grossman, J. & McMahon, M. Dysfunctional, pro-inflammatory HDL directly upregulates monocyte PDGFRβ, chemotaxis and TNFα production. Clin. Immunol. 137, 147–156 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Charles-Schoeman, C. et al. Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. Arthritis Rheum. 60, 2870–2879 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cruz, D. et al. Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy. J. Clin. Invest. 118, 2917–2928 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Holven, K. B. et al. The antiatherogenic function of HDL is impaired in hyperhomocysteinemic subjects. J. Nutr. 138, 2070–2075 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Charakida, M. et al. Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. JAMA 302, 1210–1217 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Atkinson, D. & Small, D. M. Recombinant lipoproteins: implications for structure and assembly of native lipoproteins. Annu. Rev. Biophys. Biophys. Chem. 15, 403–456 (1986).

    Article  CAS  PubMed  Google Scholar 

  97. Patel, S. et al. Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. J. Am. Coll. Cardiol. 53, 962–971 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Peshavariya, H. et al. Reconstituted high-density lipoprotein suppresses leukocyte NADPH oxidase activation by disrupting lipid rafts. Free Radic. Res. 43, 772–782 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Nobécourt, E. et al. Nonenzymatic glycation impairs the antiinflammatory properties of apolipoprotein A-I. Arterioscler. Thromb. Vasc. Biol. 30, 766–772 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. McGrath, K. C. et al. Role of 3β-hydroxysteroid-Δ24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 29, 877–882 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Patel, S. et al. Anti-inflammatory effects of apolipoprotein A-I in the rabbit. Atherosclerosis 212, 392–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Tabet, F. et al. The 5A apolipoprotein A-I mimetic peptide displays anti-inflammatory and antioxidant properties in vivo and in vitro. Arterioscler. Thromb. Vasc. Biol. 30, 246–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Smythies, L. E. et al. Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macrophages. Am. J. Physiol. Cell Physiol. 298, C1538–C1548 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dai, L. et al. The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats. J. Lipid Res. 51, 2695–2705 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Woo, J. M. et al. Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis. Arthritis Res. Ther. 12, R93 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Wool, G. D. et al. 4F peptide reduces nascent atherosclerosis and induces natural antibody production in apolipoprotein E-null mice. FASEB J. 25, 290–300 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bielicki, J. K. et al. A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice. J. Lipid Res. 51, 1496–1503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ruchala, P. et al. Oxpholipin 11D: an anti-inflammatory peptide that binds cholesterol and oxidized phospholipids. PLoS ONE 5, e10181 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by USPHS Grant HL 30568, and the Laubisch Fund and M. K. Gray Fund at UCLA.

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M. Navab and A. M. Fogelman contributed to discussion of content for the article, researched data to include in the manuscript, wrote the article, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments. S. T. Reddy and B. J. Van Lenten reviewed and edited the manuscript before submission.

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Correspondence to Mohamad Navab.

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Competing interests

M. Navab and S. T. Reddy are principals in Bruin Pharmaceuticals, and A. M. Fogelman is an officer for Bruin Pharmaceuticals. B. J. Van Lenten declares no competing interests.

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Navab, M., Reddy, S., Van Lenten, B. et al. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 8, 222–232 (2011). https://doi.org/10.1038/nrcardio.2010.222

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