Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec, Canada.
J Am Coll Cardiol. 2010 Jun 8;55(23):2580-9. doi: 10.1016/j.jacc.2010.02.035.
The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels in vitro and in vivo.
Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease.
HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production. For in vivo studies, African green monkeys (AGMs) received 15 to 60 mg/kg/day RVX-208, and the serum was analyzed for lipoprotein levels, HDL-subparticle distribution, cholesterol efflux, and activity of lipid-modifying enzymes. A phase I clinical trial was conducted in healthy volunteers (given 1 to 20 mg/kg/day of RVX-208) to assess safety, tolerability, and pharmacokinetics.
The RVX-208 induced apoA-I messenger ribonucleic acid and protein synthesis in HepG2 cells, leading to increased levels of pre-beta-migrating and alpha-lipoprotein particles containing apoA-I (LpA-I) in spent media. Similarly, in AGMs, RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels (60% and 97%, respectively). In addition, the levels of pre-beta(1)-LpA-I and alpha1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette AI, adenosine triphosphate binding cassette G1, and scavenger receptor class B type I-dependent cholesterol efflux. These changes were not mediated by cholesteryl-ester-transfer protein. Treatment of humans for 1 week with oral RVX-208 increased apoA-I, pre-beta-HDL, and HDL functionality.
RVX-208 increases apoA-I and HDL-C in vitro and in vivo. In AGMs, RVX-208 raises serum pre-beta(1)-LpA-I and alpha-LpA-I levels and enhances cholesterol efflux. Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis.
本研究旨在确定新型小分子 RVX-208 对体外和体内载脂蛋白（apo）A-I 和高密度脂蛋白胆固醇（HDL-C）水平的影响。
apoA-I 和 HDL-C 水平升高是降低动脉粥样硬化疾病的潜在治疗靶点。
用 0 至 60μmol/L RVX-208 处理 HepG2 细胞，然后检测 apoA-I 和 HDL-C 的产生。对于体内研究，非洲绿猴（AGM）接受 RVX-208 15 至 60mg/kg/天的治疗，分析血清中的脂蛋白水平、HDL 亚颗粒分布、胆固醇流出和脂质修饰酶的活性。在健康志愿者中进行了一项 I 期临床试验（给予 1 至 20mg/kg/天的 RVX-208），以评估安全性、耐受性和药代动力学。
RVX-208 诱导 HepG2 细胞中的 apoA-I 信使核糖核酸和蛋白质合成，导致培养上清液中富含 apoA-I 的前-β-迁移和α-脂蛋白颗粒（LpA-I）水平增加。同样，在 AGM 中，RVX-208 治疗 63 天可增加血清 apoA-I 和 HDL-C 水平（分别增加 60%和 97%）。此外，前-β1-LpA-I 和α1-LpA-I HDL 亚颗粒的水平也增加了，同时还有 ATP 结合盒 AI、ATP 结合盒 G1 和清道夫受体 B 型 I 依赖性胆固醇流出。这些变化不是由胆固醇酯转移蛋白介导的。人类口服 RVX-208 治疗 1 周可增加 apoA-I、前-β-HDL 和 HDL 功能。
RVX-208 可增加体外和体内的 apoA-I 和 HDL-C。在 AGM 中，RVX-208 可提高血清前-β1-LpA-I 和α-LpA-I 水平并增强胆固醇流出。人类的数据表明 RVX-208 具有有益的特性，可能对治疗动脉粥样硬化有用。
