KLF14 and Atherosclerosis

KLF14 与动脉粥样硬化

• 批准号: 9333689
• 负责人: YUQING Eugene CHEN
• 金额: $ 70.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333689
• 关键词: ATP-Binding Cassette Transporters; Animal Model; Antiatherogenic; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Back; Binding Sites; Biological Markers; Biological Process; Blood Circulation; Cause of Death; Cholesterol; Clinical; Clinical Trials; Coronary heart disease; Data; Development; Diabetes Mellitus; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Event; Excision; Formulation; Frequencies; Genetic; Goals; Heart failure; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Impairment; Infusion procedures; LDL Cholesterol Lipoproteins; Lipids; Liver; Liver X Receptor; Mediating; Membrane; Mus; Organ; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Prevention; Production; Promoter Regions; Property; Receptor Activation; Regulation; Role; Safety; Side; Techniques; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; United States; Up-Regulation; base; design; disability; genome wide association study; in vivo; knock-down; loss of function; macrophage; nanoparticle; novel; novel therapeutics; particle; prevent; reverse cholesterol transport; targeted delivery; targeted treatment; treatment strategy

ABSTRACT Reverse cholesterol transport (RCT) is an important protective mechanism against atherosclerosis, in which plasma high-density lipoprotein cholesterol (HDL-c) interacts with macrophages in arterial wall and shuttles excess of cholesterol back to the liver. In macrophages, the cholesterol efflux activity is controlled by the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Upregulation of ABCA1/ABCG1 in macrophages increases cholesterol efflux activity to HDL particles and decreases atherosclerosis. Kruppel- like factor 14 (KLF14), identified by large genome-wide association studies, is strongly associated with HDL-c level, coronary heart disease (CHD). Our preliminary studies demonstrate that KLF14 increases plasma HDL-c level by modulating hepatic apolipoprotein (apoA-I) production. Intriguingly, we identified that perhexiline, which is clinically used to treat angina and heart failure, is a novel KLF14 activator. Perhexiline-mediated KLF14 activation attenuated atherosclerosis in apoE-deficiency mice. Interestingly, we found that KLF14 regulates cholesterol efflux by upregulation of ABCA1 and ABCG1 in macrophages, which contribute to the availability of cholesterol to apoA-I and HDL. However, perhexiline has sub-optimal pharmaceutical properties such as off-target toxicity, narrow therapeutic index and variable pharmacokinetics. We also demonstrated that synthetic high density lipoprotein (sHDL) nanoparticles could target delivery of drugs to atheroma. These sHDL has been tested in clinical trials at large doses and were found to be safe and have favorable pharmacokinetics. Furthermore, we have developed sHDL-mediated drug delivery platform for atherosclerosis treatment. In this proposal, we will: 1) Determine KLF14 regulates atherosclerotic regression by enhancing cholesterol efflux; 2) Develop sHDL nanoparticles as an efficient atheroma drug delivery system; 3) Determine the ability of sHDL nanoparticles mediated KLF14 activator delivery to promote atherosclerosis regression in vivo. The long-term goal of this project is to understand the function and underlying mechanism of KLF14 in atherosclerosis regression in order to design novel therapeutic strategies for treatment of atherosclerosis.

摘要 胆固醇逆向转运（RCT）是抗动脉粥样硬化的重要保护机制，其中 血浆高密度脂蛋白胆固醇（HDL-c）与动脉壁巨噬细胞相互作用， 过量的胆固醇回到肝脏。在巨噬细胞中，胆固醇流出活性由 ATP结合盒（ABC）转运蛋白ABCA 1和ABCG 1的表达。ABCA 1/ABCG 1的上调 在巨噬细胞中增加胆固醇流出到HDL颗粒的活性并减少动脉粥样硬化。克虏伯- 通过大规模全基因组关联研究发现，类因子14（KLF 14）与HDL-c密切相关 水平，冠心病（CHD）。我们的初步研究表明，KLF 14增加血浆HDL-c， 通过调节肝载脂蛋白（apoA-I）的产生来降低水平。有趣的是，我们发现了perhexiline， 临床上用于治疗心绞痛和心力衰竭，是一种新的KLF 14激活剂。哌克西林介导 活化KLF 14可减轻apoE缺乏小鼠的动脉粥样硬化。有趣的是，我们发现KLF 14 通过上调巨噬细胞中的ABCA 1和ABCG 1来调节胆固醇流出，这有助于 胆固醇对apoA-I和HDL的利用率。然而，perhexiline具有次优的药物特性 例如脱靶毒性、狭窄治疗指数和可变的药代动力学。我们还证明了 合成的高密度脂蛋白（sHDL）纳米颗粒可以靶向动脉粥样硬化的药物输送。这些sHDL 已在临床试验中以大剂量进行了测试，发现是安全的，并具有良好的药代动力学。 此外，我们还开发了sHDL介导的动脉粥样硬化治疗药物输送平台。在这 我们将：1）确定KLF 14通过增强胆固醇流出来调节动脉粥样硬化消退; 2） 开发sHDL纳米粒作为有效的动脉粥样硬化药物递送系统; 3）测定sHDL 纳米颗粒介导的KLF 14激活剂递送促进体内动脉粥样硬化消退。长期 该项目的目标是了解KLF 14在动脉粥样硬化中的功能和潜在机制 回归，以便设计用于治疗动脉粥样硬化的新的治疗策略。