Identification of KU-55933 as an anti- atherosclerosis compound by using a hemodynamic-based high- throughput drug screening platform

• 成果类型: Article
• 署名作者: Wei, Shu-Yi; Fu, Wei-Shan; Liu, Chang-Hsuan; Wang, Wei-Li; Shih, Yu-Tsung; Chien, Shu; Chiu, Jeng-Jiann
• 署名单位: National Health Research Institutes - Taiwan; Taipei Medical University; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Taipei Medical University; Taipei Medical University; National Tsing Hua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14957
• DOI: 10.1073/pnas.2318718121
• 发表日期: 2024-01-30
• 关键词: bone morphogenetic protein; shear-stress; endothelial dysfunction; disturbed flow; inhibition; cells; proliferation; activation; expression; mechanism

摘要

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti- atherosclerotic drugs based on hemodynamic force- mediated atherogenesis have been discovered. Our previous studies demonstrated that small mothers against decapentaplegic homolog 1/5 (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti- atherosclerosis drug development. The goal of this study was to develop a high- throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP- induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id - 1) as a luciferase reporter, we demonstrated that KU - 55933 and Apicidin suppressed Id - 1 expression in AD - 293 cells. KU - 55933 (10 mu M), Apicidin (10 mu M), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4- induced Smad1/5 activation in human vascular endothelial cells (ECs). KU- 55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU - 55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU - 55933 and 1/2(K + A) to apolipoprotein E- deficient mice inhibited Smad1/5 activation in ECs in athero- susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU - 55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.