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Biological Properties of Apolipoprotein A-I Mimetic Peptides

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Abstract

Apolipoprotein A-I (apoA-I) mimetic peptides resemble the physiochemical properties of the helices of apoA-I and show promise for the treatment of atherosclerotic vascular diseases and other chronic inflammatory disorders. These peptides have numerous properties, such as the ability to remodel high-density lipoprotein, sequester oxidized lipids, promote cholesterol efflux, and activate an anti-inflammatory process in macrophages, any or all of which may contribute to their antiatherogenic properties. In murine models, the 4F peptide attenuates early atherosclerosis but seems to require the addition of statins to influence more mature lesions. A recently developed method for the oral delivery of the peptides that protects them from proteolysis will facilitate further research on the mechanism of action of these peptides. This review focuses on the properties of the 4F peptide, although numerous apoA-I mimetics are under investigation and a single “best” peptide that mimics all of the properties of the antiatherogenic protein apoA-I has not been identified.

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References

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

  1. Davidson WS, Silva RA, Chantepie S, et al.: Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol 2009, 29:870–876.

    Article  CAS  PubMed  Google Scholar 

  2. Vaisar T, Pennathur S, Green PS, et al.: Shotgun proteomics implicates protease inhibition and complement activation in the anti-inflammatory properties of HDL. J Clin Invest 2007, 117:595–598.

    Article  Google Scholar 

  3. deGoma EM, deGoma RL, Rader DJ: Beyond high-density lipoprotein cholesterol levels. J Am Coll Cardiol 2008, 51:2199–2211.

    Article  CAS  PubMed  Google Scholar 

  4. Miyazaki A, Sakuma S, Morikawa W, 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 

  5. Anantharamaih GM, Jones JL, Brouillette CG, et al.: Studies of synthetic peptide analogs of the amphipathic helix. Structure of complexes with dimyristoyl phosphatidycholine. J Biol Chem 1985, 260:10248–10255.

    Google Scholar 

  6. Yancey PG, Bielicki JK, Johnson WJ, et al.: Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides. Biochemistry 1995, 34:7955–7965.

    Article  CAS  PubMed  Google Scholar 

  7. Getz GS, Wool GD, Reardon CA: Apoprotein A-I mimetic peptides and their potential anti-atherogenic mechanisms of action. Curr Opin Lipidol 2009, 20:171–175.

    Article  CAS  PubMed  Google Scholar 

  8. Navab M, Anantharamaiah GM, Reddy ST, et al.: Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol 2005, 25:1325–1331.

    Article  CAS  PubMed  Google Scholar 

  9. Anantharamaiah GM, Mishra VK, Garber GW, et al.: Structural requirements for anti-oxidative an anti-inflammatory properties of apolipoprotein A-I mimetic peptides. J Lipid Res 2007, 48:1915–1923.

    Article  CAS  PubMed  Google Scholar 

  10. Navab M, Anantharamaiah GM, Hama S, et al.: Oral administration of an apoA-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 

  11. Van Lenten BJ, Wagner AC, Navab M, et al.: Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits. J Lipid Res 2007, 48:2344–2353.

    Article  PubMed  Google Scholar 

  12. Ou J, Ou Z, Jones DW, et al.: L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease. Circulation 2003, 107:2337–2341.

    Article  CAS  PubMed  Google Scholar 

  13. Wool GD, Vaisar T, Reardon CA, Getz GS: An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide. J Lipid Res 2009, 50:1889–1900.

    Article  CAS  PubMed  Google Scholar 

  14. Li X, Chyu KY, Faria Neto JR, et al.: Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 2004, 110:1701–1705.

    Article  CAS  PubMed  Google Scholar 

  15. Navab M, Anantharamaiah GM, Hama S, et al.: D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2005, 25:1426–1432.

    Article  CAS  PubMed  Google Scholar 

  16. •• Navab M, Ruchala P, Waring AJ, et al.: A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids. J Lipid Res 2009, 50:1538–1547. This article demonstrates that the co-administration of mimetic peptides and niclosamide increases the bioavailability and plasma levels of mimetic peptides synthesized with L-amino acids, likely by preventing the proteolysis of the peptides in the gut.

    Article  CAS  PubMed  Google Scholar 

  17. Navab M, Anantharamaiah GM, Fogelman AM: The effect of apolipoprotein mimetic peptides in inflammatory disorders other than atherosclerosis. Trends Cardiovasc Med 2008, 18:61–66.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang Z, Datta G, Zhang Y, et al.: Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats. Am J Physiol Heart Circ Physiol 2009, 297:H866–H873.

    Article  CAS  PubMed  Google Scholar 

  19. Navab, M, Hama SY, Anantharamaiah GM, 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 2000, 41:1495–1508.

    CAS  PubMed  Google Scholar 

  20. Navab M, Anantharamaiah GM, Reddy ST, 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 

  21. Ansell BJ, Navab M, Hama S, et al.: 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 2003, 108:2751–2756.

    Article  CAS  PubMed  Google Scholar 

  22. Garber DW, Datta G, Chaddha M, et al.: A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J Lipid Res 2001, 42:545–552.

    CAS  PubMed  Google Scholar 

  23. •• Van Lenten BJ, Wagner AC, Jung CL, 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 article demonstrates that 4F binds to oxidized phospholipids and fatty acids, but not nonoxidized lipids, with significantly higher affinity than apoA-I. This property of the peptides is likely an important mechanism responsible for their anti-inflammatory effects. The affinity of L4F and D4F for the oxidized lipids was similar.

    Article  PubMed  Google Scholar 

  24. Navab M, Anantharamaiah GM, Reddy ST, et al.: Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 2004, 109:3215–3220.

    Article  CAS  PubMed  Google Scholar 

  25. Navab M, Berliner JA, Subbanagounder G, et al.: HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol 2001, 21:481–488.

    CAS  PubMed  Google Scholar 

  26. Zhao L, Funk CD: Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med 2004, 14:191–195.

    Article  CAS  PubMed  Google Scholar 

  27. • Poeckel D, Zemski Berry KA, Murphy RC, Funk CD: Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in apoE knockout mice. J Biol Chem 2009, 284:21077–21089. This article demonstrates that the loss of lipoxygenase activity, a major source of oxidized lipids, decreases atherosclerosis, consistent with the proatherogenic role of these oxidized lipids.

    Article  CAS  PubMed  Google Scholar 

  28. Cyrus T, Witztum JL, Rader DJ, et al.: Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apoE-deficient mice. J Clin Invest 1999, 103:1597–1604.

    Article  CAS  PubMed  Google Scholar 

  29. Buga GM, Frank JS, Mottino, et al.: D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet. J Lipid Res 2008, 49:192–205.

    Article  CAS  PubMed  Google Scholar 

  30. Ou J, Wang J, Xu H, et al.: 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 2005, 97:1190–1197.

    Article  CAS  PubMed  Google Scholar 

  31. • Wool GD, Reardon CA, Getz GS: Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties. J Lipid Res 2008, 49:1268–1283. This article demonstrates that tandem 4F peptides promote cholesterol efflux to a greater extent than the 4F monomer, and that tandem 4F peptides remodel HDL more efficiently than the monomer.

    Article  CAS  PubMed  Google Scholar 

  32. Sethi AA, Stonik JA, Thomas F, et al.: Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides. J Biol Chem 2008, 283:32273–32282.

    Article  CAS  PubMed  Google Scholar 

  33. Tang C, Vaughan AM, Anantharamaiah GM, Oram JF: Janus kinase 2 modulates the lipid-removing but not protein-stabilizing interactions of amphipathic helices with ABCA1. J Lipid Res 2006, 47:107–114.

    Article  CAS  PubMed  Google Scholar 

  34. •• Tang C, Liu Y, Kessler PS, et al.: The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem 2009, 284:32336–32343. This article demonstrates that the interaction of apoA-I and mimetic peptides with ABCA1 activates the JAK2/STAT3 pathway in macrophages, leading to an anti-inflammatory phenotype.

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Garber DW, Venkatachalapathi YV, Gupta KB, et al.: Turnover of synthetic class A amphipathic peptide analogues of exchangeable apolipoproteins in rats. Correlation with physical properties. Arterioscler Thromb 1992, 12:886–894.

    CAS  PubMed  Google Scholar 

  37. Handattu SP, Garber DW, Horn DC, et al.: ApoA-I mimetic peptides with differing ability to inhibit atherosclerosis also exhibit differences in their interactions with membrane bilayers. J Biol Chem 2007, 282:1980–1988.

    Article  CAS  PubMed  Google Scholar 

  38. Tam SP, Ancsin JB, Tan R, Kisilevsky R: Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE-/- mice. J Lipid Res 2005, 46:2091–2101.

    Article  CAS  PubMed  Google Scholar 

  39. Navab M, Anantharamaiah GM, Reddy ST, et al.: Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in apoE null mice. Circ Res 2005, 97:524–532.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, The University of Chicago, MC 1089, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA

    Godfrey S. Getz, Geoffrey D. Wool & Catherine A. Reardon

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  1. Godfrey S. Getz
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  2. Geoffrey D. Wool
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  3. Catherine A. Reardon
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Correspondence to Godfrey S. Getz.

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Getz, G.S., Wool, G.D. & Reardon, C.A. Biological Properties of Apolipoprotein A-I Mimetic Peptides. Curr Atheroscler Rep 12, 96–104 (2010). https://doi.org/10.1007/s11883-010-0097-4

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