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Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 540–547 (2006)Cite this article

Abstract

The importance of apolipoprotein A-I (apoA-I) in atherosclerosis was established by testing in animal models, and its potential usefulness in humans has been confirmed in preliminary studies. ApoA-I is a large protein comprising 243 amino acids, which means that venous administration is necessary. In addition, manufacture of apoA-I is difficult and expensive. Research has, therefore, been directed towards finding smaller peptide mimetics that produce similar results to apoA-I, but that are easier to manufacture and administer. The earliest peptides mimicked some of the lipid-binding properties of apoA-I but did not prevent atherosclerosis in mice. A detailed study of the physical–chemical characteristics of these peptides led to the realization that the hydrophobic region of the peptide was critical in determining bioactivity. A potent peptide, 4F, which was synthesized wholly from D-amino acids, could be given orally. Use of 4F significantly improved the function of HDL in mice and monkeys. When 4F was administered in combination with a statin, lesion size and macrophage content were reduced in mice with atherosclerosis, and lesions regressed in older mice. Vasoreactivity and endothelial sloughing were also improved in other rodent studies. Early human clinical trials are now being carried out on 4F. Here, we review the studies on apoA-I mimetic peptides that have been carried out so far.

Key Points

  • A potent apolipoprotein A-I mimetic peptide, 4F, that could be given orally was synthesized wholly from D-amino acids

  • Use of 4F significantly improved the function of HDL in mice and monkeys

  • When administered in combination with a statin, atherosclerotic lesion size and macrophage content were reduced in mice and lesions regressed in older mice

  • Vasoreactivity and endothelial sloughing were improved in a rat model of diabetes

  • Early human clinical trials are in progress using D-4F

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Figure 1: A potential mechanism of action by the D-4F apoA-I mimetic peptide on HDL recycling and function in humans.

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References

  1. Badimon JJ et al. (1990) Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest 85: 1234–1241

    Article  CAS  Google Scholar 

  2. Plump AS et al. (1994) 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

    Article  CAS  Google Scholar 

  3. Chiesa G and Sirtori CR (2002) Use of recombinant apolipoproteins in vascular diseases: the case of apoA-I. Curr Opin Investig Drugs 3: 420–426

    CAS  PubMed  Google Scholar 

  4. Nanjee MN et al. (1999) Acute effects of intravenous infusion of apoA-I/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vasc Biol 19: 979–989

    Article  CAS  Google Scholar 

  5. Nanjee MN et al. (2001) Intravenous apoA-I/lecithin discs increase pre-β-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res 42: 1586–1593

    CAS  PubMed  Google Scholar 

  6. Kujiraoka T et al. (2003) Effects of intravenous apolipoprotein A-I/phosphatidylcholine discs on LCAT, PLTP, and CETP in plasma and peripheral lymph in humans. Arterioscler Thromb Vasc Biol 23: 1653–1659

    Article  CAS  Google Scholar 

  7. Nissen SE et al. (2003) Effect of recombinant apoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290: 2292–2300

    Article  CAS  Google Scholar 

  8. Rader DJ (2003) High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA 290: 2322–2324

    Article  CAS  Google Scholar 

  9. Zhang Y et al. (2003) Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo. Circulation 108: 661–663

    Article  CAS  Google Scholar 

  10. Barter PJ et al. (2004) Anti-inflammatory properties of HDL. Circ Res 95: 764–772

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Navab M et al. (2000) 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

    CAS  PubMed  Google Scholar 

  13. Navab M et al. (2004) The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res 45: 993–1007

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Navab M et al. (2005) An oral apoJ peptide renders HDL anti-inflammatory in mice and monkeys and dramatically reduces atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 25: 1932–1937

    Article  CAS  Google Scholar 

  16. Ansell BJ et al. (2003) Inflammatory/anti-inflammatory 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

    Article  CAS  Google Scholar 

  17. Berliner JA and Watson AD (2005) A role for oxidized phospholipids in atherosclerosis. N Engl J Med 353: 9–11

    Article  CAS  Google Scholar 

  18. Tsimikas S et al. (2005) Oxidized phospholipids Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 353: 46–57

    Article  CAS  Google Scholar 

  19. Lusis AJ et al. (2004) Genetic basis of atherosclerosis: part I. Circulation 110: 1868–1873

    Article  Google Scholar 

  20. Anantharamaiah GM et al. (1985) Studies of synthetic peptide analogs of amphipathic helix: structure of complexes with dimyristoyl phosphatidylcholine. J Biol Chem 260: 10248–10255

    CAS  PubMed  Google Scholar 

  21. Anantharamaiah GM (1986) Synthetic peptide analogs of apolipoproteins. Methods Enzymol 128: 627–647

    Article  CAS  Google Scholar 

  22. Yancey PG et al. (1995) Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides. Biochemistry 34: 7955–7965

    Article  CAS  Google Scholar 

  23. Venkatachalapathi YV et al. (1993) Effect of end group blockage on the properties of a class A amphipathic helical peptide. Proteins 15: 349–359

    Article  CAS  Google Scholar 

  24. Datta G et al. (2001) Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. J Lipid Res 42: 1096–1104

    CAS  PubMed  Google Scholar 

  25. Navab M et al. (2005) Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol 25: 1325–1331

    Article  CAS  Google Scholar 

  26. Reddy ST et al. (2006) Oral amphipathic peptides as therapeutic agents. Expert Opin Investig Drugs 15: 13–21

    Article  CAS  Google Scholar 

  27. Tang C et al. (2006) Janus kinase 2 modulates the lipid-removing but not protein-stabilizing interactions of amphipathic helices with ABCA1. J Lipid Res 47: 107–114

    Article  CAS  Google Scholar 

  28. Navab M et al. (2001) HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol 21: 481–488

    Article  CAS  Google Scholar 

  29. Forte TM et al. (2002) Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet activating factor acetylhydrolase in atherosclerosis-susceptible mice. J Lipid Res 43: 477–485

    Article  CAS  Google Scholar 

  30. Van Lenten BJ et al. (2001) The role of high-density lipoproteins in oxidation and inflammation. Trends Cardiovasc Med 11: 155–161

    Article  CAS  Google Scholar 

  31. Fogelman AM (2004) When good cholesterol goes bad. Nat Med 10: 902–903

    Article  CAS  Google Scholar 

  32. Navab M et al. (2005) The role of high-density lipoprotein in inflammation. Trends Cardiovasc Med 15: 158–161

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Nicholls SJ et al. (2005) Formation of dysfunctional high-density lipoprotein by myeloperoxidase. Trends Cardiovasc Med 15: 212–219

    Article  CAS  Google Scholar 

  35. Ansell BJ et al. (2005) High-density lipoprotein function recent advances. J Am Coll Cardiol 46: 1792–1798

    Article  CAS  Google Scholar 

  36. Moore RE et al. (2005) Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circ Res 97: 763–771

    Article  CAS  Google Scholar 

  37. Navab M et al. (2002) Oral administration of an apoA-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 105: 290–292

    Article  CAS  Google Scholar 

  38. Van Lenten BJ et al. (2001) High-density lipoprotein loses its anti-inflammatory properties during acute influenza A infection. Circulation 103: 2283–2288

    Article  CAS  Google Scholar 

  39. Van Lenten BJ et al. (2002) Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation 106: 1127–1132

    Article  CAS  Google Scholar 

  40. Van Lenten BJ et al. (2004) D-4F, an apolipoprotein A-I mimetic peptide, inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes. Circulation 110: 3252–3258

    Article  CAS  Google Scholar 

  41. Srinivas RV et al. (1990) Antiviral effects of apolipoprotein A-I and its synthetic amphipathic peptide analogs. Virology 176: 48–57

    Article  CAS  Google Scholar 

  42. Navab M et al. (2004) 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

    Article  CAS  Google Scholar 

  43. Li X et al. (2004) Differential effects of apolipoprotein A-I mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 110: 1701–1705

    Article  CAS  Google Scholar 

  44. Shah PK and Chyu KY (2005) Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management. Trends Cardiovasc Med 15: 291–296

    Article  CAS  Google Scholar 

  45. Navab M et al. (2005) D-4F and statins synergize to render HDL anti-inflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 25: 1426–1432

    Article  CAS  Google Scholar 

  46. Ou Z et al. (2003) L-4F, an apolipoprotein mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells. Circulation 107: 1520–1524

    Article  CAS  Google Scholar 

  47. Ou J et al. (2003) L-4F, an apolipoprotein A-I mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease. Circulation 107: 2337–2341

    Article  CAS  Google Scholar 

  48. Ou J et al. (2005) Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet. Circ Res 97: 1190–1197

    Article  CAS  Google Scholar 

  49. Navab M et al. (2005) An apolipoprotein A-I mimetic works best in the presence of apolipoprotein A-I. Circ Res 97: 1085–1086

    Article  CAS  Google Scholar 

  50. Kruger AL et al. (2005) D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes. Circulation 111: 3126–3134

    Article  CAS  Google Scholar 

  51. Duffy D and Rader DJ (2005) Drugs in development: targeting high-density lipoprotein metabolism and reverse cholesterol transport. Curr Opin Cardiol 20: 301–306

    Article  Google Scholar 

  52. Linsel-Nitschke P and Tall AR (2005) HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov 4: 193–205

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants HL-30568 to AM Fogelman, HL-34343 to GM Anantharamaiah, and the Laubisch, Castera, and MK Grey Funds at UCLA to AM Fogelman.

Author information

Authors and Affiliations

  1. professors, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Mohamad Navab & Alan M Fogelman

  2. an associate professor in the Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Srinivasa T Reddy

  3. a professor in the Department of Medicine, University of Alabama, Birmingham, AL, USA

    GM Anantharamaiah

Authors
  1. Mohamad Navab
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  2. GM Anantharamaiah
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  3. Srinivasa T Reddy
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  4. Alan M Fogelman
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Corresponding author

Correspondence to Mohamad Navab.

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Competing interests

Mohamad Navab, GM Anantharamaiah and Srinivasa T Reddy are Principals and Alan M Fogelman is an Officer in BruinPharma, a start-up biotech company.

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Navab, M., Anantharamaiah, G., Reddy, S. et al. Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention. Nat Rev Cardiol 3, 540–547 (2006). https://doi.org/10.1038/ncpcardio0661

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