An octimibate derivative, Oxa17, enhances cholesterol efflux and exerts anti-inflammatory and atheroprotective effects in experimental atherosclerosis

• Published in: Biochemical pharmacology Vol. 188; p. 114581
• Main Authors: Tsui, Pi-Fen, Chern, Ching-Yuh, Lien, Chih-Feng, Lin, Feng-Yen, Tsai, Chien-Sung, Tsai, Min-Chien, Lin, Chin-Sheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.06.2021
• Subjects: Atherosclerosis; Cholesterol efflux; Inflammation; Liver X receptor; Macrophage; Octimibate derivative; Liver X receptor; Inflammation; Octimibate derivative; Atherosclerosis; Cholesterol efflux; Macrophage
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114581

[Display omitted] 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.