Abstract 679: Oral Administration of Compound RVX-208 Increases Serum Levels of ApoA-I and Improves High-Density Lipoprotein-Mediated Cholesterol Efflux in African Green Monkeys
High-density lipoprotein (HDL) is believed to be a potent physiological protective system against atherosclerotic cardiovascular disease through its pivotal role in the reverse cholesterol transport process. Overexpression or repeated infusion of apoA-I inhibits progression and induces regression of atherosclerosis in animals and humans. A strong therapeutic rationale therefore exists for increasing serum apoA-I levels; however, a major limitation in the use of apoA-I or apoA-I mimetic peptides as pharmacological agents has been the need for parenteral administration. In the present study, we examined the effects of oral administration of RVX-208 on serum apoA-I levels, HDL subspecies distribution and the ability of serum to promote cholesterol efflux. African green monkeys received RVX-208 (60 mg/kg/day) or vehicle control for 28 days. Oral administration of RVX-208 for 28 days produced a significant increase in serum apoA-I levels, compared with vehicle control monkeys (133 to 153 mg/dl vs. 134 to 203 mg/dl; p < 0.05; values are for basal and at day 28 of vehicle or RVX-208 treatments, respectively). Analysis of apoA-I-containing particles by 2D-gels revealed that RVX-208 treatment caused a 3-fold increase in pre(beta)1-LpA-I levels. Furthermore, there was a significant increase in the largest (HDL-2b) particles compared to vehicle control monkeys. To assess the effect of RVX-208 treatment on the ability of serum to promote cholesterol efflux via ABCA1 pathway, J774 macrophages were labelled with 3H-cholesterol and the fractional cholesterol efflux in monkey serum was determined. Serum from RVX-208-treated monkeys promoted significantly greater cholesterol efflux from cAMP-stimulated J774 cells, as compared to serum from vehicle control monkeys (+40% ± 8; n = 4). Taken together, these data indicate that in vivo treatment with RVX-208 caused a significant increase in serum apoA-I levels and especially the proportion of apoA-I in pre(beta)1-LpA-I particles, which improves HDL’s ability to mediate cholesterol efflux via the ABCA1 pathway. Further investigation of the effect of RVX-208 on the HDL metabolic pathway is ongoing to establish the mechanisms of action and therapeutic potential in treating atherosclerotic cardiovascular disease.