KLF14 and 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。 血浆高密度脂蛋白胆固醇(hdl-c)与动脉壁巨噬细胞和穿梭细胞的相互作用 过量的胆固醇回到肝脏。在巨噬细胞中，胆固醇外流活动受 三磷酸腺苷结合盒(ABC)转运蛋白ABCA1和Abcg1的表达ABCA1/Abcg1基因上调 在巨噬细胞中，增加胆固醇向高密度脂蛋白颗粒的流出活性，并减少动脉粥样硬化。克鲁佩尔- 像因子14(KLF14)一样，被大规模的全基因组关联研究所确定，与高密度脂蛋白-c密切相关 冠心病(CHD)。我们的初步研究表明，KLF14可升高血浆高密度脂蛋白-c 通过调节肝脏载脂蛋白(apoA-I)的产生来提高载脂蛋白水平。耐人寻味的是，我们发现了全己胺， 临床上用于治疗心绞痛和心力衰竭，是一种新型的KLF14激活剂。培己胺介导剂 KLF14激活减轻载脂蛋白E缺陷小鼠的动脉粥样硬化。有趣的是，我们发现KLF14 通过上调巨噬细胞中ABCA1和Abcg1的表达来调节胆固醇的外流，这有助于 胆固醇对载脂蛋白A-I和高密度脂蛋白的利用率。然而，培己胺的药用性能并不理想。 如脱靶毒性、狭窄的治疗指数和可变的药代动力学。我们还展示了 合成的高密度脂蛋白(SHDL)纳米颗粒可以靶向向动脉粥样硬化输送药物。这些shdl 已经在大剂量的临床试验中进行了测试，并被发现是安全的，具有良好的药代动力学。 此外，我们还开发了用于动脉粥样硬化治疗的sHDL介导的药物释放平台。在这 建议，我们将：1)确定KLF14通过促进胆固醇外流来调节动脉粥样硬化的消退；2) 开发shdl纳米粒作为动脉粥样硬化的有效给药系统；3)测定shdl的能力。 纳米粒介导KLF14激活剂在体内促进动脉粥样硬化消退。长期的 本项目的目标是了解KLF14在动脉粥样硬化中的功能和潜在机制 回归，以设计治疗动脉粥样硬化的新治疗策略。

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.