DOI QR코드

DOI QR Code

LJ-1888, a selective antagonist for the A3 adenosine receptor, ameliorates the development of atherosclerosis and hypercholesterolemia in apolipoprotein E knock-out mice

  • Park, Jong-Gil (Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Jeong, Se-Jin (Cardiovascular Division, Department of Medicine, Washington University School of Medicine) ;
  • Yu, Jinha (College of Pharmacy, Seoul National University) ;
  • Kim, Gyudong (College of Pharmacy, Seoul National University) ;
  • Jeong, Lak Shin (College of Pharmacy, Seoul National University) ;
  • Oh, Goo Taeg (Immune and Vascular Cell Network Research Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans University)
  • Received : 2018.04.30
  • Accepted : 2018.05.21
  • Published : 2018.10.31

Abstract

Cardiovascular diseases arising from atherosclerosis are the leading causes of mortality and morbidity worldwide. Lipid-lowering agents have been developed in order to treat hypercholesterolemia, a major risk factor for atherosclerosis. However, the prevalence of cardiovascular diseases is increasing, indicating a need to identify novel therapeutic targets and develop new treatment agents. Adenosine receptors (ARs) are emerging as therapeutic targets in asthma, rheumatoid arthritis, cancer, ischemia, and inflammatory diseases. This study assessed whether LJ-1888, a selective antagonist for $A_3$ AR, can inhibit the development of atherosclerosis in apolipoprotein E knock-out ($ApoE^{-/-}$) mice who are fed a western diet. Plaque formation was significantly lower in $ApoE^{-/-}$ mice administered LJ-1888 than in mice not administered LJ-1888, without any associated liver damage. LJ-1888 treatment of $ApoE^{-/-}$ mice prevented western diet-induced hypercholesterolemia by markedly reducing low-density lipoprotein cholesterol levels and significantly increasing high-density lipoprotein cholesterol concentrations. Reduced hypercholesterolemia in $ApoE^{-/-}$ mice administered LJ-1888 was associated with the enhanced expression of genes involved in bile acid biosynthesis. These findings indicate that LJ-1888, a selective antagonist for $A_3$ AR, may be a novel candidate for the treatment of atherosclerosis and hypercholesterolemia.

Keywords

Atherosclerosis;High-density lipoprotein cholesterol (HDL-chol);Hypercholesterolemia;Low-density lipoprotein cholesterol (LDL-chol);LJ-1888

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Korea Research Institute of Bioscience and Biotechnology

References

  1. Heseltine L, Webster JM and Taylor R (1995) Adenosine effects upon insulin action on lipolysis and glucose transport in human adipocytes. Mol Cell Biochem 144, 147-151 https://doi.org/10.1007/BF00944394
  2. Bingham TC, Fisher EA, Parathath S, Reiss AB, Chan ES and Cronstein BN (2010) A2A adenosine receptor stimulation decreases foam cell formation by enhancing ABCA1-dependent cholesterol efflux.J Leukoc Biol 87, 683-690 https://doi.org/10.1189/jlb.0709513
  3. Jones MR, Zhao Z, Sullivan CP et al (2004) A(3) adenosine receptor deficiency does not influence atherogenesis. J Cell Biochem 92, 1034-1043 https://doi.org/10.1002/jcb.20122
  4. Yu J, Ahn S, Kim HJ et al (2017) Polypharmacology of N(6)-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and Related A3 Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) gamma Partial Agonist and PPARdelta Antagonist Activity Suggests Their Antidiabetic Potential. J Med Chem 60, 7459-7475 https://doi.org/10.1021/acs.jmedchem.7b00805
  5. Park HJ, Kim MK, Kim Y et al (2017) Gastrin-releasing peptide promotes the migration of vascular smooth muscle cells through upregulation of matrix metalloproteinase-2 and -9. BMB Rep 50, 628-633 https://doi.org/10.5483/BMBRep.2017.50.12.158
  6. Jung HJ, Im SS, Song DK, Bae JH (2017) ffects of chlorogenic acid on intracellular calcium regulation in lysophosphatidylcholine-treated endothelial cells. BMB Rep 50, 323-328 https://doi.org/10.5483/BMBRep.2017.50.6.182
  7. Chiang JY (2009) Bile acids: regulation of synthesis. J Lipid Res 50, 1955-1966 https://doi.org/10.1194/jlr.R900010-JLR200
  8. Chiang JY, Kimmel R, Weinberger C and Stroup D (2000) Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J Biol Chem 275, 10918-10924 https://doi.org/10.1074/jbc.275.15.10918
  9. Bonovas S, Nikolopoulos G and Sitaras NM (2011) Efficacy and safety of more intensive lowering of LDL cholesterol. Lancet 377, 715; author reply 715-716
  10. Tobert JA (2003) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2, 517-526 https://doi.org/10.1038/nrd1112
  11. Pedersen TR and Tobert JA (1996) Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal. Drug Saf 14, 11-24 https://doi.org/10.2165/00002018-199614010-00003
  12. Dembowski E and Davidson MH (2009) Statin and ezetimibe combination therapy in cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 16, 183-188 https://doi.org/10.1097/MED.0b013e3283295297
  13. Michos ED, Sibley CT, Baer JT, Blaha MJ and Blumenthal RS (2012) Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials. J Am Coll Cardiol 59, 2058-2064 https://doi.org/10.1016/j.jacc.2012.01.045
  14. Leiva A, Guzman-Gutierrez E, Contreras-Duarte S et al (2017) Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels. Mol Aspects Med 55, 26-44 https://doi.org/10.1016/j.mam.2017.01.007
  15. Reiss AB and Cronstein BN (2012) Regulation of foam cells by adenosine. Arterioscler Thromb Vasc Biol 32, 879-886 https://doi.org/10.1161/ATVBAHA.111.226878
  16. Ohisalo JJ (1981) Effects of adenosine on lipolysis in human subcutaneous fat cells. J Clin Endocrinol Metab 52, 359-363 https://doi.org/10.1210/jcem-52-2-359
  17. Chen JF, Eltzschig HK and Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 12, 265-286 https://doi.org/10.1038/nrd3955
  18. Jacobson KA (1998) Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol Sci 19, 184-191 https://doi.org/10.1016/S0165-6147(98)01203-6
  19. Borea PA, Varani K, Vincenzi F et al (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67, 74-102
  20. Jeong LS, Choe SA, Gunaga P et al (2007) Discovery of a new nucleoside template for human A3 adenosine receptor ligands: D-4'-thioadenosine derivatives without 4'-hydroxymethyl group as highly potent and selective antagonists. J Med Chem 50, 3159-3162 https://doi.org/10.1021/jm070259t
  21. Lee J, Hwang I, Lee JH, Lee HW, Jeong LS and Ha H (2013) The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis. Am J Pathol 183, 1488-1497 https://doi.org/10.1016/j.ajpath.2013.07.010
  22. Libby P, Ridker PM and Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317-325 https://doi.org/10.1038/nature10146
  23. Libby P, Schoenbeck U, Mach F, Selwyn AP and Ganz P (1998) Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization. Am J Med 104, 14S-18S
  24. Istvan ES and Deisenhofer J (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160-1164 https://doi.org/10.1126/science.1059344
  25. Hou R and Goldberg AC (2009) Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety. Endocrinol Metab Clin North Am 38, 79-97 https://doi.org/10.1016/j.ecl.2008.11.007
  26. Lee MR, Lim CJ, Lee YH et al (2014) The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice. Nat Commun 5, 4410 https://doi.org/10.1038/ncomms5410
  27. Nissen SE, Tuzcu EM, Schoenhagen P et al (2005) Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352, 29-38 https://doi.org/10.1056/NEJMoa042000
  28. Davis HR Jr, Compton DS, Hoos L and Tetzloff G (2001) Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol 21, 2032-2038 https://doi.org/10.1161/hq1201.100260
  29. Smith L, Mosley J, Yates J and Caswell L (2016) The New Face of Hyperlipidemia Management: Proprotein Convertase Subtilisin/Kexin Inhibitors (PCSK-9) and Their Emergent Role As An Alternative To Statin Therapy. J Pharm Pharm Sci : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 19, 137-146
  30. Brousseau ME, Schaefer EJ, Wolfe ML et al (2004) Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 350, 1505-1515 https://doi.org/10.1056/NEJMoa031766
  31. White CR, Datta G, Zhang Z et al (2008) HDL therapy for cardiovascular diseases: the road to HDL mimetics. Curr Atheroscler Rep 10, 405-412 https://doi.org/10.1007/s11883-008-0063-6
  32. Writing Group M, Mozaffarian D, Benjamin EJ et al (2016) Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 133, e38-360
  33. Layland J, Carrick D, Lee M, Oldroyd K and Berry C (2014) Adenosine: physiology, pharmacology, and clinical applications. JACC Cardiovasc Interv 7, 581-591 https://doi.org/10.1016/j.jcin.2014.02.009
  34. Bowser JL, Lee JW, Yuan X and Eltzschig HK (2017) The hypoxia-adenosine link during inflammation. J Appl Physiol 123, 1303-1320 https://doi.org/10.1152/japplphysiol.00101.2017
  35. Sheth S, Brito R, Mukherjea D, Rybak LP and Ramkumar V (2014) Adenosine receptors: expression, function and regulation.Int J Mol Sci 15, 2024-2052 https://doi.org/10.3390/ijms15022024
  36. Nelson RH (2013) Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care 40, 195-211 https://doi.org/10.1016/j.pop.2012.11.003
  37. Jeong SJ, Lee MN and Oh GT (2017) The Role of Macrophage Lipophagy in Reverse Cholesterol Transport. Endocrinol Metab 32, 41-46 https://doi.org/10.3803/EnM.2017.32.1.41
  38. Weber C and Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17, 1410-1422 https://doi.org/10.1038/nm.2538
  39. Hebert PR, Gaziano JM, Chan KS and Hennekens CH (1997) Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. Jama 278, 313-321 https://doi.org/10.1001/jama.1997.03550040069040
  40. Pignone M, Phillips C and Mulrow C (2000) Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 321, 983-986 https://doi.org/10.1136/bmj.321.7267.983
  41. Cheung BM and Lam KS (2010) Is intensive LDLcholesterol lowering beneficial and safe? Lancet 376, 1622-1624 https://doi.org/10.1016/S0140-6736(10)61545-0