Abstract 493: Antiatherosclerotic Activity of a New P2y13 Receptor Agonist (ct1007900) in Animal Models

Abstract

The F1-ATPase/P2Y13 receptor pathway has been involved in the regulation of the HDL uptake liver and disposition via the reverse cholesterol transport. CT1007900 is a novel selective P2Y13 receptor agonist that has been shown to enhance the HDL uptake that results in the increased secretion of the bile acid, bile cholesterol and bile phospholipid into the gallbladder in mice. In the present study, CT1007900 has been evaluated in three different animal models of atherosclerosis. In ApoE -/- flow cessation model, the administration of the drug decreased the cholesterol concentration in atherosclerotic plaques. In a high fat diet fed ApoE -/- mouse model, the prevention of the progression of the plaque in aorta was further evaluated after 4-week treatment with CT1007900. The treated animals had significant decreases in plaque area, cholesterol content, VCAM1 expression and macrophage content. In the high fat diet fed rabbits, 4-week treatment reduced the cholesterol content by about 30% and also decreased the thickness of the plaques. The ApoA1 mRNA levels in the liver and ApoA1 protein concentration in the plasma increased in the drug-treated animals. The HDL content of the treated animals showed a very consistent pattern with a specific decrease in large HDL and an increase of the “intermediate” size HDL particles as compared to control animals. These intermediate HDL particles seem to be more efficient particles for the removal of cholesterol from atherosclerotic plaques by increasing efflux of cholesterol from the macrophages present in the lesions. The plasma samples from drug treated rabbits showed a dose-dependent increase in the cholesterol efflux in an in vitro assay using J774 cells. These results clearly demonstrate that improving functionality of HDL rather than the levels of HDL could have a positive impact on the atherosclerotic pathology. These data also support that P2Y13 receptor agonists could be useful pharmacological therapeutics for the treatment of complications due to atherosclerotic disease.