Document Type : Review Article


1 Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

2 Biomedical Laboratory, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia


Background: HDL has been identified a s a p otential n ew t reatment f or atherosclerosis. Targeting lipid metabolism via the Reverse Cholesterol Transport (RCT) pathway can improve HDL metabolism. Apolipoprotein A-I mimetic peptides (ApoA-I MPs) are able to increase HDL metabolism. Thus, this systematic review aimed to examine the potential effect o f A poA-I M Ps a gainst a therosclerosis i n mice models through the RCT mechanism.
METHOD: This systematic review was conducted using previous in vivo studies published in four scientific databases over the last ten years (PubMed, SCOPUS, ProQuest, and Science Direct) and was based on the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) protocol. 
RESULTS: This study’s primary outcome was a reduction in atherosclerotic plaque, where 16 articles were qualified for this study. Based on the risk of bias analysis, these articles had a low risk of bias. Most in vivo studies (13 of 16) showed that ApoA-I MPs significantly reduced atherosclerotic plaque formation. Generally, ApoA-I MPs played an important role in regulating HDL metabolism (HDL remodeling process, increased cholesterol efflux, and stimulated RCT pathway) and anti-inflammatory agent. ApoA-I MPs may differ in their ability to reduce atherosclerotic plaque depending on the peptide sequence and administration route.
CONCLUSIONS: ApoA-I MPs can reduce atherosclerotic plaque formation in mice by increasing cholesterol efflux vi a th e RC T pa thway. Fu rther in vestigation is re quired to su pport th e de velopment of ApoA-I MPs as a new therapy for atherosclerosis in humans.


  1. Kim H, Kim S, Han S, Rane PP, Fox KM, Qian Y, et al. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: A nationwide population-based study. BMC Public Health. 2019; 19(1): 1–11.
  2. Khera A V., Rader DJ. Future therapeutic directions in reverse cholesterol transport. Curr Atheroscler Rep. 2010; 12(1): 73–81.
  3. Getz GS, Wool GD, Reardon CA. Biological properties of apolipoprotein A-I mimetic peptides. Curr Atheroscler Rep. 2010; 12(2): 96–104.
  4. Leman LJ, Maryanoff BE, Ghadiri MR. Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem. 2014; 57(6): 2169–96.
  5. Sherman CB, Peterson SJ, Frishman WH. Apolipoprotein A-I mimetic peptides: A potential new therapy for the prevention of atherosclerosis. Cardiol Rev. 2010; 18(3): 141–7.
  6. Leenaars M, Hooijmans CR, van Veggel N, ter Riet G, Leeflang M, Hooft L, et al. A step-by-step guide to systematically identify all relevant animal studies. Lab Anim. 2012; 46(1): 24–31.
  7. Hooijmans CR, Rovers MM, De Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014; 14(1): 1–9.
  8. Navab M, Reddy ST, Anantharamaiah GM, Imaizumi S, Hough G, Hama S, et al. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally. J Lipid Res. 2011; 52(6): 1200–10.
  9. Ou ZJ, Li L, Liao XL, Wang YM, Hu XX, Zhang QL, et al. Apolipoprotein A-I mimetic peptide inhibits atherosclerosis by altering plasma metabolites in hypercholesterolemia. Am J Physiol - Endocrinol Metab. 2012; 303(6): 683–94.
  10. Li R, Navab M, Pakbin P, Ning Z, Navab K, Hough G, et al. Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant capacity in LDLR-null mice. J Lipid Res. 2013; 54(6): 1608–15.
  11. Tian H, Yao S-T, Yang N-N, Ren J, Jiao P, Zhang X, et al. D4F alleviates macrophage-derived foam cell apoptosis by inhibiting the NF-κB-dependent Fas/FasL pathway. Sci Rep. 2017; 7(1): 7333.
  12. Qin S, Kamanna VS, Lai JH, Liu T, Ganji SH, Zhang L, et al. Reverse D4F, an apolipoprotein-AI mimetic peptide, inhibits atherosclerosis in ApoE-null mice. J Cardiovasc Pharmacol Ther. 2012; 17(3): 334–43.
  13. Wu G, Wei W, Zhang J, Nie W, Yuan L, Huang Y, et al. A self-driven bioinspired nanovehicle by leukocyte membrane-hitchhiking for early detection and treatment of atherosclerosis. Biomaterials [Internet]. 2020; 250: 119963. Available from:
  14. Ying R, Yuan Y, Qin Y-F, Tian D, Feng L, Guo Z-G, et al. The combination of L-4F and simvastatin stimulate cholesterol efflux and related proteins expressions to reduce atherosclerotic lesions in apoE knockout mice. Lipids Health Dis. 2013; 12: 180.
  15. Averill MM, Kim EJ, Goodspeed L, Wang S, Subramanian S, Den Hartigh LJ, et al. The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice. PLoS One. 2014; 9(10): e109252.
  16. Chattopadhyay A, Navab M, Hough G, Gao F, Meriwether D, Grijalva V, et al. A novel approach to oral apoA-I mimetic therapy. J Lipid Res. 2013; 54(4): 995–1010.
  17. Ditiatkovski M, D’Souza W, Kesani R, Chin-Dusting J, de Haan JB, Remaley A, et al. An apolipoprotein A-I mimetic peptide designed with a reductionist approach stimulates reverse cholesterol transport and reduces atherosclerosis in mice. PLoS One. 2013; 8(7): e68802.
  18. Ditiatkovski M, Palsson J, Chin-Dusting J, Remaley AT, Sviridov D. Apolipoprotein A-I Mimetic Peptides: Discordance between in Vitro and in Vivo Properties - Brief Report. Arterioscler Thromb Vasc Biol. 2017; 37(7): 1301–6.
  19. Suematsu Y, Kawachi E, Idemoto Y, Matsuo Y, Kuwano T, Kitajima K, et al. Anti-atherosclerotic effects of an improved apolipoprotein A-I mimetic peptide. Int J Cardiol [Internet]. 2019; 297: 111–7. Available from:
  20. Uehara Y, Ando S, Yahiro E, Oniki K, Ayaori M, Abe S, et al. FAMP, a Novel ApoA-I Mimetic Peptide, Suppresses Aortic Plaque Formation Through Promotion of Biological HDL Function in ApoE-Deficient Mice. J Am Heart Assoc. 2013; 2(3): 1–15.
  21. Zhao Y, Black AS, Bonnet DJ, Maryanoff BE, Curtiss LK, Leman LJ, et al. In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I. J Lipid Res. 2014; 55(10): 2053–63.
  22. Schwendeman A, Sviridov DO, Yuan W, Guo Y, Morin EE, Yuan Y, et al. The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties. J Lipid Res. 2015; 56(9): 1727–37.
  23. Edmunds SJ, Liébana-García R, Nilsson O, Domingo-Espín J, Grönberg C, Stenkula KG, et al. ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice. Diabetologia. 2019; 62(7): 1257–67.

.24.     Dunbar RL, Movva R, Bloedon LT, Duffy D, Norris RB, Navab M, et al. Oral Apolipoprotein A‐I Mimetic D‐4F Lowers HDL‐Inflammatory Index in High‐Risk Patients: A First‐in‐Human Multiple‐Dose, Randomized Controlled Trial. Clin Transl Sci. 2017; 10(6): 455–69.

  1. Amar MJA, D’Souza W, Turner S, Demosky S, Sviridov D, Stonik J, et al. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J Pharmacol Exp Ther. 2010; 334(2): 634–41.
  2. Linton MF, Yancey PG, Davies SS, Jerome WG, Linton EF, Song WL, et al. The Role of Lipids and Lipoproteins in Atherosclerosis [Internet]. Feingold K, Anawalt B, Boyce A, et al., editors. South Dartmouth: Endotext [Internet]; 2019. Available from:
  3. Ikenaga M, Higaki Y, Saku K, Uehara Y. High-Density Lipoprotein Mimetics: a Therapeutic Tool for Atherosclerotic Diseases. J Atheroscler Thromb. 2016; 23(4): 385–94.
  4. Getz GS, Reardon CA. Apolipoprotein A-I and A-I mimetic peptides: a role in atherosclerosis. J Inflamm Res. 2011; 4: 83–92.
  5. Zhou Z, Subramanian P, Sevilmis G, Globke B, Soehnlein O, Karshovska E, et al. Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium. Cell Metab. 2011; 13(5): 592–600.

30.       Gou S, Wang L, Zhong C, Chen X, Ouyang X, Li B, et al. A novel apoA-I mimetic peptide suppresses atherosclerosis bypromoting physiological HDL function in apoE−/−mice. Br J Pharmacol. 2020; 177: 4627–4644.