Gilham Dean, Wasiak Sylwia, Tsujikawa Laura M, Halliday Christopher, Norek Karen, Patel Reena G, Kulikowski Ewelina, Johansson Jan, Sweeney Michael, Wong Norman C W, Gordon Allan, McLure Kevin, Young Peter
Resverlogix Corp., Calgary, Canada.
Resverlogix Corp., San Francisco, USA.
Atherosclerosis. 2016 Apr;247:48-57. doi: 10.1016/j.atherosclerosis.2016.01.036. Epub 2016 Jan 22.
High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.
高密度脂蛋白（HDL）通过其主要蛋白质成分载脂蛋白A-I（ApoA-I）的活性，可从动脉粥样硬化斑块中清除多余胆固醇，从而降低心血管疾病（CVD）风险。在本研究中，我们证明，溴结构域和额外末端结构域（BET）抑制剂RVX-208可增加人和灵长类原代肝细胞中ApoA-I基因转录及蛋白质生成。相应地，在最近完成的2b期试验SUSTAIN和ASSURE中，接受该化合物治疗的患者体内，RVX-208也显著提高了ApoA-I水平、HDL相关胆固醇水平及HDL颗粒数量。此外，一项事后分析显示，接受RVX-208治疗的患者发生主要不良心脏事件的情况较少。为了解RVX-208对心血管疾病风险相关生物学过程的影响，我们对离体处理的人原代肝细胞和全血进行了微阵列分析。总体而言，数据表明，RVX-208可提高ApoA-I/HDL水平，并抑制可能导致CVD风险的促炎、促动脉粥样硬化和促血栓形成途径。
