Skip to main content
SpringerLink
Log in

Recombinant High-Density Lipoprotein Formulations

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

High-density lipoprotein cholesterol (HDL-C) has emerged as a biomarker of residual cardiovascular disease (CVD) risk in high-risk patients treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapies inclusive of inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase. The evidence for increasing low levels of HDL-C is sparse, and the available data are confounded by metabolic interactions between elevated very low-density lipoprotein (VLDL) and LDL particle concentrations. Despite these limitations, there has been widespread interest in novel strategies that target HDL. One such path has been the development of recombinant HDL formulations that mimic the pre-beta fraction of native HDL, which is the main HDL subclass that mediates cholesterol efflux from lipid-laden macrophages. Various recombinant HDL formulations (apolipoprotein A-1 [apoA-1]-bound phospholipid disks or delipidated HDL particles, mutant apoA-1 proteins, and apoA-1 mimetic peptides) have been investigated in animal studies and some human trials. However, these HDL-modifying therapies require evaluation in clinical trials of atherosclerosis and CVD events. This review presents our current knowledge on novel recombinant therapies, and their future prospects to mitigate atherosclerotic CVD events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Dahlöf B: Cardiovascular disease risk factors: Epidemiology and risk assessment. Am J Cardiol 2010, 105:3A–9A.

    Article  PubMed  Google Scholar 

  2. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977, 62:707–714.

    Article  CAS  PubMed  Google Scholar 

  3. Rosenson RS: Low HDL-C: A secondary target of dyslipidemia therapy. Am J Med 2005, 118:1067–1077.

    Article  CAS  PubMed  Google Scholar 

  4. Gotto AM, Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ et al: Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas coronary atherosclerosis prevention study (AFCAPS/TexCAPS). Circulation 2000, 101:477–484.

    CAS  PubMed  Google Scholar 

  5. Otvos JD, Jeyarajah EJ, Cromwell WC: Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002, 90:22–29.

    Article  Google Scholar 

  6. Navab M, Anantharamaiah G, Reddy S, Van Lenten B, Fogelman A: HDL as a biomarker, potential therapeutic target, and therapy. Diabetes 2009, 58:2711.

    Article  CAS  PubMed  Google Scholar 

  7. •• deGoma EM, deGoma RL, Rader DJ: Beyond high-density lipoprotein cholesterol levels: Evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Col Cardiol 2008, 51:2199–2211. This review outlines approaches used in the assessment of HDL function and potential application in evaluation of HDL therapies.

    Article  Google Scholar 

  8. Natarajan P, Ray KK, Cannon CP: High-Density Lipoprotein and coronary heart disease: Current and future therapies. J Am Coll of Cardiol 2010, 55:1283–1299.

    Article  CAS  Google Scholar 

  9. Khera AV, Rader DJ: Future therapeutic directions in reverse cholesterol transport. Curr Atheroscler Rep 2010, 12:73–81.

    Article  CAS  PubMed  Google Scholar 

  10. Calabresi L, Gomaraschi M, Rossoni G, Franceschini G: Synthetic high density lipoproteins for the treatment of myocardial ischemia/reperfusion injury. Pharmacology & Therapeutics 2006, 111:836–854.

    Article  CAS  Google Scholar 

  11. Kruit JK, Brunham LR, Verchere CB, Hayden MR: HDL and LDL cholesterol significantly influence beta-cell function in type 2 diabetes mellitus. Curr Opin Lipidol 2010, 21:178–185.

    Article  CAS  PubMed  Google Scholar 

  12. •• Yu B-l, Wang S-h, Peng D-q, Zhao S-p: HDL and immunomodulation: an emerging role of HDL against atherosclerosis. Immunol Cell Biol 2010, 88:285–290. This review describes the emerging role of HDL in immunomodulation.

    Article  CAS  PubMed  Google Scholar 

  13. Orekhov A, Misharin A, Tertov V, Khashimov K, Pokrovsky S, Repin V, Smirnov V: Artificial HDL as an anti-atherosclerotic drug. Lancet 1984, 2:1149.

    Article  CAS  PubMed  Google Scholar 

  14. Badimon JJ, Badimon L, Galvez A, Dische R, Fuster V: High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest 1989, 60:455–461.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Miyazaki A, Sakuma S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H, Sakamoto Y-I, Naito M et al: Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 1995, 15:1882–1888.

    CAS  PubMed  Google Scholar 

  17. Dimayuga P, Zhu J, Oguchi S, Chyu KY, Xu XO, Yano J, Shah PK, Nilsson J, Cercek B: Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoE null mice. Biochem Biophys Res Commun 1999, 264:465–468.

    Article  CAS  PubMed  Google Scholar 

  18. Cockerill GW, Huehns TY, Weerasinghe A, Stocker C, Lerch PG, Miller NE, Haskard DO: Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation 2001, 103:108–112.

    CAS  PubMed  Google Scholar 

  19. Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye KA, Barter PJ: Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 2005, 111:1543–1550.

    Article  CAS  PubMed  Google Scholar 

  20. Rossoni G, Gomaraschi M, Berti F, Sirtori CR, Franceschini G, Calabresi L: Synthetic high-density lipoproteins exert cardioprotective effects in myocardial ischemia/reperfusion injury. J Pharmacol Exp Ther 2004, 308:79–84.

    Article  CAS  PubMed  Google Scholar 

  21. Tso C, Martinic G, Fan W-H, Rogers C, Rye K-A, Barter PJ: High-Density lipoproteins enhance progenitor-mediated endothelium repair in mice. Arterioscler Thromb Vasc Biol 2006, 26:1144–1149.

    Article  CAS  PubMed  Google Scholar 

  22. Eriksson M, Carlson LA, Miettinen TA, Angelin B: Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation 1999, 100:594–598.

    CAS  PubMed  Google Scholar 

  23. Nanjee MN, Doran JE, Lerch PG, Miller NE: Acute effects of intravenous infusion of ApoA1/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vasc Biol 1999, 19:979–989.

    CAS  PubMed  Google Scholar 

  24. Nanjee MN, Cooke CJ, Garvin R, Semeria F, Lewis G, Olszewski WL, Miller NE: Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res 2001, 42:1586–1593.

    CAS  PubMed  Google Scholar 

  25. Spieker LE, Sudano I, Hurlimann D, Lerch PG, Lang MG, Binggeli C, Corti R, Ruschitzka F, Luscher TF, Noll G: High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002, 105:1399–1402.

    Article  CAS  PubMed  Google Scholar 

  26. Tardif JC, Gregoire J, L’Allier PL, Ibrahim R, Lesperance J, Heinonen TM, Kouz S, Berry C, Basser R, Lavoie MA et al: Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007, 297:1675–1682.

    Article  PubMed  Google Scholar 

  27. •• Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, Woollard K, Lyon S, Sviridov D, Dart AM: Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res 2008, 103:1084–1091. This is a clinical study in patients with peripheral artery disease demonstrating that one intravenous infusion of rHDL (80 mg/kg) prior to peripheral atherectomy and revascularization led to acute changes of plaque lipid content and inflammatory markers.

    Article  CAS  PubMed  Google Scholar 

  28. Patel S, Drew BG, Nakhla S, Duffy SJ, Murphy AJ, Barter PJ, Rye KA, Chin-Dusting J, Hoang A, Sviridov D 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 2009, 53:962–971.

    Article  CAS  PubMed  Google Scholar 

  29. • Calkin AC, Drew BG, Ono A, Duffy SJ, Gordon MV, Schoenwaelder SM, Sviridov D, Cooper ME, Kingwell BA, Jackson SP: Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation 2009, 120:2095–2104. This is a study elucidating a mechanistic explanation for the effect of HDL in the inhibition on platelet aggregation in type 2 diabetic patients.

    Article  CAS  PubMed  Google Scholar 

  30. Franceschini G, Sirtori CR, Bosisio E, Gualandri V, Battista Orsini G, Mogavero AM, Capurso A: Relationship of the phenotypic expression of the A-IMilano apoprotein with plasma lipid and lipoprotein patterns. Atherosclerosis 1985, 58:159–174.

    Article  CAS  PubMed  Google Scholar 

  31. Gualandri V, Franceschini G, Sirtori C, Gianfranceschi G, Orsini G, Cerrone A, Menotti A: AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission. Am J Hum Genet 1985, 37:1083.

    Google Scholar 

  32. Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, Salvetti M, Monteduro C, Zulli R, Muiesan ML et al: Cardiovascular status of carriers of the apolipoprotein A-IMilano mutant : The Limone sul Garda Study. Circulation 2001, 103:1949–1954.

    CAS  PubMed  Google Scholar 

  33. Franceschini G, Calabresi L, Chiesa G, Parolini C, Sirtori CR, Canavesi M, Bernini F: Increased cholesterol efflux potential of sera from ApoA-IMilano carriers and transgenic mice. Arterioscler Thromb Vasc Biol 1999, 19:1257–1262.

    CAS  PubMed  Google Scholar 

  34. Favari E, Gomaraschi M, Zanotti I, Bernini F, Lee-Rueckert M, Kovanen P, Sirtori C, Franceschini G, Calabresi L: A unique protease-sensitive high density lipoprotein particle containing the apolipoprotein A-IMilano dimer effectively promotes ATP-binding cassette A1-mediated cell cholesterol efflux. J Biol Chem 2007, 282:5125.

    Article  CAS  PubMed  Google Scholar 

  35. Weibel GL, Alexander ET, Joshi MR, Rader DJ, Lund-Katz S, Phillips MC, Rothblat GH: Wild-type apoA-I and the milano variant have similar abilities to stimulate cellular lipid mobilization and efflux. Arterioscler Thromb Vasc Biol 2007, 27:2022–2029.

    Article  CAS  PubMed  Google Scholar 

  36. Bielicki JK, Oda MN: Apolipoprotein A-IMilano and Apolipoprotein A-IParis exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-I. Biochemistry 2002, 41:2089–2096.

    Article  CAS  PubMed  Google Scholar 

  37. Shah PK, Nilsson J, Kaul S, Fishbein MC, Ageland H, Hamsten A, Johansson J, Karpe F, Cercek B: Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation 1998, 97:780–785.

    CAS  PubMed  Google Scholar 

  38. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, Drake S, Cercek B: High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization. Circulation 2001, 103:3047–3050.

    Article  CAS  PubMed  Google Scholar 

  39. Chiesa G, Monteggia E, Marchesi M, Lorenzon P, Laucello M, Lorusso V, Di Mario C, Karvouni E, Newton RS, Bisgaier CL et al: Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res 2002, 90:974–980.

    Article  CAS  PubMed  Google Scholar 

  40. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL et al: Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003, 290:2292–2300.

    Article  CAS  PubMed  Google Scholar 

  41. Parolini C, Marchesi M, Lorenzon P, Castano M, Balconi E, Miragoli L, Chaabane L, Morisetti A, Lorusso V, Martin B: Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-IMilano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: In vivo assessment by intravascular ultrasound and magnetic resonance imaging. J Am Coll Cardiol 2008, 51:1098.

    Google Scholar 

  42. Ibanez B, Vilahur G, Cimmino G, Speidl WS, Pinero A, Choi BG, Zafar MU, Santos-Gallego CG, Krause B, Badimon L 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 2008, 51:1104–1109.

    Google Scholar 

  43. Chyu K-Y, Yano J, Li X, Zhou J, Lio WM, Chan C, Dimayuga PC, Cercek B, Nykiforuk CL, Shen Y: Safflower seed-derived des-1,2-apoA1Milano reduces atherosclerosis in hypercholesterolemic apolipoprotein e (-/-) mice. J Am Col Cardiol 2010, 55:A50.E478.

    Article  Google Scholar 

  44. Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, Martin BD, Perlman TJ, Maltais JAB, Weissman NJ et al: A First-in-Man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Col Cardiol 2010, 55:2727–2735.

    Article  Google Scholar 

  45. Smith JD: Dysfunctional HDL as a diagnostic and therapeutic target. Arterioscler Thromb Vasc Biol 2010, 30:151–155.

    Article  CAS  PubMed  Google Scholar 

  46. Datta G, Chaddha M, Hama S, Navab M, Fogelman AM, Garber DW, Mishra VK, Epand RM, Epand RF, Lund-Katz S et al: Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. J Lipid Res 2001, 42:1096–1104.

    CAS  PubMed  Google Scholar 

  47. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, Lallone R, Fogelman AM: Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002, 105:290–292.

    Article  CAS  PubMed  Google Scholar 

  48. Bloedon LT, Dunbar R, Duffy D, Pinell-Salles P, Norris R, DeGroot BJ, Movva R, Navab M, Fogelman AM, Rader DJ: Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res 2008, 49:1344–1352.

    Article  CAS  PubMed  Google Scholar 

  49. Van Lenten BJ, Wagner AC, Jung C-L, Ruchala P, Waring AJ, Lehrer RI, Watson AD, Hama S, Navab M, Anantharamaiah GM et al: Anti-inflammatory apoA-I-mimetic peptides bind oxidized lipids with much higher affinity than human apoA-I. J Lipid Res 2008, 49:2302–2311. This is a study showing that that 4F possess 4 to 6 orders of magnitude higher oxidized lipid binding capacity than apoA-I, thereby providing an explanation for its anti-inflammatory properties.

    Article  PubMed  Google Scholar 

  50. Imaizumi S, Grijalva V, Navab M, Van Lenten BJ, Wagner AC, Anantharamiah GM, Fogelman AM, Reddy ST: L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL in mice. Drug Metab Lett 2010, 4:139–148.

    Article  CAS  PubMed  Google Scholar 

  51. Mendez AJ, Anantharamaiah GM, Segrest JP, Oram JF: Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol. J Clin Invest 1994, 94:1698–1705.

    Article  CAS  PubMed  Google Scholar 

  52. • Tabet F, Remaley AT, Segaliny AI, Millet J, Yan L, Nakhla S, Barter PJ, Rye KA, Lambert G: The 5A Apolipoprotein A-I Mimetic Peptide Displays Antiinflammatory and Antioxidant Properties In Vivo and In Vitro. Arterioscler Thromb Vasc Biol 2010, 30:246–252. This article demonstrates, in vivo and in vitro, that the 5A peptide complexed to phospholipids displays antioxidant and anti-inflammatory properties similar to those of apoA-I, whereas the 5A peptide shares a similar mechanism with apoA-1.

    Article  CAS  PubMed  Google Scholar 

  53. Amar MJA, D’Souza W, Turner S, Demosky S, Sviridov D, Stonik J, Luchoomun J, Voogt J, Hellerstein M, Sviridov D et al: 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J Pharmacol Exp Ther 2010, 334:634–641.

    Article  CAS  PubMed  Google Scholar 

  54. Gupta H, White CR, Handattu S, Garber DW, Datta G, Chaddha M, Dai L, Gianturco SH, Bradley WA, Anantharamaiah GM: Apolipoprotein E mimetic peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits. Circulation 2005, 111:3112–3118.

    Article  CAS  PubMed  Google Scholar 

  55. Datta G, White CR, Dashti N, Chaddha M, Palgunachari MN, Gupta H, Handattu SP, Garber DW, Anantharamaiah GM: Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide, Ac-hE18A-NH2. Atherosclerosis 2010, 208:134–141.

    Article  CAS  PubMed  Google Scholar 

  56. Bielicki JK, Zhang H, Cortez Y, Zheng Y, Narayanaswami V, Patel A, Johansson J, Azhar S: A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice. J Lipid Res 2010, 51:1496–1503.

    Article  CAS  PubMed  Google Scholar 

  57. Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Wagner AC, Hama S, Hough G, Bachini E, Garber DW, Mishra VK et al: An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E-Null Mice. Arterioscler Thromb Vasc Biol 2005, 25:1932–1937.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

Robert S. Rosenson has no potential conflict of interest to report. Esad Vucic has no potential conflict of interest to report.

Author information

Authors and Affiliations

  1. The Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY, 10029, USA

    Robert S. Rosenson

  2. Translational and Molecular Imaging Institute, Imaging Science Laboratories, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Esad Vucic

  3. Cardiometabolic Disorders, Mount Sinai Heart, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Robert S. Rosenson

Authors
  1. Esad Vucic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert S. Rosenson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert S. Rosenson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vucic, E., Rosenson, R.S. Recombinant High-Density Lipoprotein Formulations. Curr Atheroscler Rep 13, 81–87 (2011). https://doi.org/10.1007/s11883-010-0141-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-010-0141-4

Keywords

Search

Navigation