Abstract 12358: Anti-Atherogenic Effect of Novel Peroxisome Proliferator-Activated Receptor δ Agonist RSC-451061 Hydrochloride Accompanied by Anti-Inflammatory Effects in LDL Receptor Knockout Mice
[Background] Atherosclerosis is considered to be a chronic inflammatory disease induced by dyslipidemia and other metabolic disorders, and the progression and instabilization of the atherosclerotic plaques induced by excess inflammation is one of the main causes of the CVD. Peroxisome Proliferator-activated Receptor (PPAR) is a member of the nuclear receptor superfamily, and it has been reported that PPARδ is closely related to the regulation of the inflammatory states. To date, however, there is no effective and safe PPAR δ agonist available for clinical use.
[Objectives] We have synthesized a novel PPARδ agonist RSC-451061 hydrochloride (RSC), and in this study, we evaluated the anti-atherogenic effect of the PPARδ agonist focused on its anti-inflammatory property in LDL receptor knockout (LDLr-KO) mice.
[Methods] Male LDLr-KO mice (n=14-15) were placed on a western diet and administrated orally with vehicle, RSC (0.03, 0.1 or 0.3 mg/kg) or fenofibrate (30 mg/kg), a PPARα agonist as a reference drug, for 18 weeks. Serum levels of lipid parameters and inflammatory markers were measured periodically. The whole aorta was excised for en face analysis, and the heart was provided for immunohistochemical analysis.
[Results] Aortic lesion area (lesion% to total aortic surface) in each treatment group was 12.27 ± 0.97% (vehicle), 11.01 ± 1.19% (0.03 mg/kg of RSC), 5.35 ± 0.63% (0.1 mg/kg of RSC), 5.31 ± 0.64% (0.3 mg/kg of RSC) and 10.77 ± 0.78 % (30 mg/kg of fenofibrate), respectively. RSC-treated groups showed significantly small aortic lesion by 56.4% (p<0.001) and 56.7% (p<0.001) as compared with vehicle-treated group at the doses of 0.1 and 0.3 mg/kg, respectively. Treatment with fenofibrate, as well as 0.03 mg/kg of RSC, did not significantly affect the aortic lesion area. MCP-1 expression and macrophage content were also decreased in the aortic lesion in RSC-treated groups. Although treatment with RSC did not affect serum lipid parameters, it significantly reduced serum MCP-1 and SAA levels, and the MCP-1-lowering effect was more potent than that of fenofibrate.
[Conclusion] A novel PPARδ agonist RSC-451061 hydrochloride showed a potent anti-atherogenic effect accompanied by anti-inflammatory effects in LDLr-KO mice.
- © 2011 by American Heart Association, Inc.