Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan; Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Department of Applied Chemistry, National Chiayi University, Chiayi City 60004, Taiwan.
Biochem Pharmacol. 2021 Jun;188:114581. doi: 10.1016/j.bcp.2021.114581. Epub 2021 Apr 23.
Atherosclerotic cardiovascular diseases (ASCVDs), associated with vascular inflammation and lipid dysregulation, are responsible for high morbidity and mortality rates globally. For ASCVD treatment, cholesterol efflux plays an atheroprotective role in ameliorating inflammation and lipid dysregulation. To develop a multidisciplinary agent for promoting cholesterol efflux, octimibate derivatives were screened and investigated for the expression of ATP-binding cassette transporter A1 (ABCA1). Western blotting and qPCR analysis were conducted to determine the molecular mechanism associated with ABCA1 expression in THP-1 macrophages; results revealed that Oxa17, an octimibate derivative, enhanced ABCA1 expression through liver X receptors alpha (LXRα) activation but not through the microRNA pathway. We also investigated the role of Oxa17 in high-fat diet (HFD)-fed mice used as an in vivo atherosclerosis-prone model. In ldlr mice, Oxa17 increased plasma high-density lipoprotein (HDL) and reduced plaque formation in the aorta. Plaque stability improved via reduction of macrophage accumulation and via narrowing of the necrotic core size under Oxa17 treatment. Our study demonstrates that Oxa17 is a novel and potential agent for ASCVD treatment with atheroprotective and anti-inflammatory properties.
动脉粥样硬化性心血管疾病（ASCVD）与血管炎症和脂质失调有关，是全球高发病率和死亡率的主要原因。对于 ASCVD 的治疗，胆固醇外排通过改善炎症和脂质失调发挥着抗动脉粥样硬化的作用。为了开发一种促进胆固醇外排的多学科药物，对奥克替米贝衍生物进行了筛选，并研究了它们对 ATP 结合盒转运蛋白 A1（ABCA1）表达的影响。通过 Western blot 和 qPCR 分析，确定了奥克替米贝衍生物 Oxa17 在 THP-1 巨噬细胞中与 ABCA1 表达相关的分子机制；结果表明，Oxa17 通过激活肝 X 受体α（LXRα）而非通过 microRNA 途径增强 ABCA1 的表达。我们还研究了 Oxa17 在高脂肪饮食（HFD）喂养的小鼠中的作用，该模型可作为体内易发生动脉粥样硬化的模型。在 ldlr 小鼠中，Oxa17 增加了血浆高密度脂蛋白（HDL）并减少了主动脉中的斑块形成。Oxa17 处理后，通过减少巨噬细胞积累和缩小坏死核心大小，改善了斑块稳定性。我们的研究表明，Oxa17 是一种新型的潜在 ASCVD 治疗药物，具有抗动脉粥样硬化和抗炎作用。
