LJ-1888, a selective antagonist for the A(3) adenosine receptor, ameliorates the development of atherosclerosis and hypercholesterolemia in apolipoprotein E knock-out mice

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 II-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 II-1888 than in mice not administered II-1888, without any associated liver damage. II-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 II-1888 was associated with the enhanced expression of genes involved in bile acid biosynthesis. These findings indicate that II-1888, a selective antagonist for A(3) AR, may be a novel candidate for the treatment of atherosclerosis and hypercholesterolemia.