LJ-1888, a selective antagonist for the A3 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 LJ-1888, a selective antagonist for A3 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 A3 AR, may be a novel candidate for the treatment of atherosclerosis and hypercholesterolemia.

Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development

“…The attenuation of the inflammatory background of atherosclerosis would be a desirable first step to treat the disease; rapidly expanding knowledge on the effects mediated by extracellular nucleotides and nucleosides on immune and non-immune cells participating in atherosclerosis will hopefully give a new chance of introducing new therapeutic compounds to treat inflammation and therefore atherosclerosis ( 93 , 149 ). Another challenge consists of finding new ways for the in situ delivery of anti-atherosclerotic drugs, to block atheroma progression and possibly revert it.…”

“…Endothelial cells use adenosinergic signaling to regulate the leakiness through the endothelial monolayer of the brain capillaries, for the passive exchange of solutes and proteins ( 89 , 90 ); however, the use of P1 agonists, particularly of the A 2A subtype has to be carefully evaluated for the side effects deriving from the T cell migration through the blood-brain barrier ( 91 ). Interestingly, A 2A receptor signaling has also been indicated as a target for limiting aneurysm formation ( 92 ); A 3 antagonism reduces hypercholesterolemia in ApoE -/- mice ( 93 ). Therefore, ADO and its receptors represent promising pharmacological targets to treat atherosclerosis.…”

Combined application of rapamycin and atorvastatin improves lipid metabolism in apolipoprotein E-deficient mice with chronic kidney disease

“…The combined use of RAPA and ATV further promoted the expression of ABCG1 and ApoA1, which contribute more to cholesterol efflux than dose RAPA or ATV alone. Given that hepatic ApoA1 synthesis decreases and HDL-C level falls are common effects of renal failure ( 34 ), our study suggests that the activation of LXRα/ApoA1/ABCG1 by RAPA and ATV co-administration improves the stability of HDL-C and atherosclerosis in CKD ( 35 , 36 ). These results suggest that the combined treatment could be synergistic in eliminating the excessive serum lipids promoting atherosclerosis, and improving general conditions and long-term mortality in mice with renal failure.…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Anti-inflammation Diabetic kidney diseases LJ-2698 [195] Atherosclerosis and hyperlipidemia LJ-1888 [196] Ischemia Protection Angina IB-MECA [197] CI-IB-MECA [198] CP-532,903 [199] Adaptation Hypertrophy Angiogenesis…”

“…The latest study shows that LJ-1888, a selective antagonist for A 3 AR, is a feasible novel candidate for the treatment of atherosclerosis and hypercholesterolemia [196]. Moreover, LJ-2698, a highly selective and species-independent A 3 AR antagonist, ameliorated diabetic kidney complications [195].…”