Abstract 12388: RSC-451061 hydrochloride, a Novel Peroxisome Proliferator-Activated Receptor Delta Agonist, Ameriorates Atherosclerotic Lesion Progression in Association with Improvement of Serum Lipid Profiles in Human ApoB100/CETP Transgenic Mouse
[Background] PPARδ is one of the transcription factors that regulate lipid metabolism. PPARδ agonists have been reported to induce the elevation of plasma HDL-C levels in obese mice, rhesus monkeys as well as humans, indicating their potentials as a new class of HDL-C raising agent. However, it is still remains unknown whether the improvement of serum lipid profile by PPARδ agonist could lead to anti-atherosclerotic effects. In this study, the effects of a novel PPARδ agonist RSC-451061 hydrochloride (RSC) on serum lipid profiles and atherosclerotic lesion progression in human apolipoprotein B-100 and cholesteryl ester transfer protein-transgenic (hApoB100/CETP-Tg) mice, which have similar serum lipoprotein profiles to humans.
[Methods] For evaluation of the effect on plasma HDL-C levels, the hApoB100/CETP-Tg mice fed with an atherogenic diet were orally treated with RSC for 3 weeks and its potency was compared with GW501516 (GW), one of the most selective and potent PPARδ agonists. For evaluation of the anti-atherosclerotic effects, the mice were orally treated with RSC for 18 weeks and atherosclerosis at the aortic valves was determined. Serum lipoprotein parameters were periodically monitored and lipoprotein profiles were analyzed by FPLC method.
[Results] Treatment with RSC resulted in significant elevation of plasma HDL-C levels with greater potency compared to GW (34% at 0.1 mg/kg/day and 27% at 3 mg/kg/day, respectively). Serum apoA-I elevation was also more potent in RSC (0.1 mg/kg/day) treatment than in GW (3 mg/kg/day) treatment (68% and 34%, respectively). The particle size of HDL was not changed by RSC treatment, suggesting that the numbers of HDL particle are increased. Long-term treatment of RSC resulted in the maximum effect to suppress atherosclerosis progression by 56% at 0.1 mg/kg/day with a strong correlation with improvement of HDL-C/nonHDL-C ratio (R=−0.73).
[Conclusion] A novel PPARδ agonist RSC-451061 hydrochloride is useful to prevent atherosclerotic lesion progression in relation to improvement of serum HDL-C/nonHDL-C ratio.
- © 2011 by American Heart Association, Inc.