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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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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
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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

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