Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates

抗 miR-33 对非人灵长类动物动脉粥样硬化消退和 RCT 的影响

• 批准号: 8438869
• 负责人: Ryan Eugene Temel
• 金额: $ 71.51万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2013-07-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438869
• 关键词: ATP-Binding Cassette Transporters; Affect; American; Antisense Oligonucleotides; Aorta; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Cells; Cercopithecus pygerythrus; Characteristics; Cholesterol; Clinical Treatment; Clinical Trials; Collagen; Complex; Coronary artery; Coronary heart disease; Feces; Fiber; Foam Cells; Future; Gene Targeting; Genes; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Homeostasis; Human; Implant; In Vitro; Inflammation; Introns; Lipids; Liver; Macaca fascicularis; Magnetic Resonance Imaging; Measures; Mediating; MicroRNAs; Molecular Sieve Chromatography; Monkeys; Mus; Patients; Process; Protein Isoforms; Proteins; Response Elements; Risk; Risk Factors; Role; Spectrometry, Mass, Electrospray Ionization; Sterols; Testing; Time; Translational Repression; fatty acid oxidation; inflammatory marker; laser capture microdissection; mRNA Transcript Degradation; macrophage; nonhuman primate; novel therapeutics; oxidation; pre-clinical; protective effect; reverse cholesterol transport; very low density lipoprotein triglyceride

Project Summary The risk of coronary heart disease (CHD), the largest major killer of Americans, is inversely associated with high-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to the role of HDL in reverse cholesterol transport (RCT), a process whereby cholesterol from macrophage foam cells in atherosclerotic plaques is effluxed to HDL, transported to the liver, and excreted in the feces. Despite intense efforts to identify new therapeutic strategies to raise HDL, this has proven to be a challenging endeavor. A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans, two isoforms of this microRNA, miR-33a and miR-33b, are encoded in introns of the sterol response element binding factor (SREBF) 2 and SREBF1 genes, and co-regulate cellular lipid homeostasis with their host genes. Notably, miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterol efflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1 (ABCA1), a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice, which encode only miR-33a, an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic and macrophage ABCA1, HDL-C, RCT, and atherosclerosis regression. However the translational value of the studies in mice was limited by the lack of miR-33b, which is expressed in humans and non-humans primates. To test the effects of inhibiting both miR-33a and b, we recently treated African green monkeys with anti-miR- 33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceride was decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33, the ability of anti-miR-33 to induce the regression of atherosclerosis in a "human-like" species expressing both miR-33a and miR-33b is still unknown. In this application, we propose to determine the effects of anti-miR-33 on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD.

项目摘要 冠心病（CHD）是美国人最大的主要杀手， 高密度脂蛋白胆固醇（HDL-C）。HDL-C的保护作用被认为是由于 HDL在胆固醇逆向转运（RCT）中的作用，这是一个胆固醇从巨噬细胞泡沫细胞 在动脉粥样硬化斑块中的高密度脂蛋白被排出到HDL，运输到肝脏，并在粪便中排泄。尽管 尽管人们一直在努力寻找新的治疗策略来提高HDL，但这已被证明是一项具有挑战性的奋进。 一个新的和有希望的增加HDL-C和RCT的靶点是microRNA-33（miR-33）。在人类中， 这种microRNA的同种型，miR-33 a和miR-33 b，在甾醇反应元件的内含子中编码 结合因子（SREBF）2和SREBF 1基因，并与其宿主基因共同调节细胞脂质稳态。 值得注意的是，miR-33 a/B诱导与胆固醇代谢相关的基因的mRNA降解和/或翻译抑制。 外排和脂肪酸氧化。miR-33 a/B的主要靶点是ATP结合盒转运蛋白A1 （ABCA 1），一种对于泡沫细胞的胆固醇流出和HDL的形成至关重要的蛋白质。在小鼠中， 仅编码miR-33 a，靶向miR-33的反义寡核苷酸（anti-miR-33）增加肝脏和 巨噬细胞ABCA 1、HDL-C、RCT和动脉粥样硬化消退。然而， 在小鼠中的研究受到缺乏miR-33 b的限制，miR-33 b在人类和非人类灵长类动物中表达。 为了测试抑制miR-33 a和B的效果，我们最近用抗miR-33 a和绿色猴子治疗。 发现肝脏ABCA 1和HDL-C升高，极低密度脂蛋白（VLDL）甘油三酯 减少了。尽管迄今为止的临床前研究结果强调了抗miR-33的心脏保护潜力， 抗miR-33在“类人”物种中诱导动脉粥样硬化消退的能力， miR-33 a和miR-33 b仍然未知。在本申请中，我们提出确定抗miR-33的作用， 在非人类灵长类动物中动脉粥样硬化消退和RCT的研究。这些研究将大大有助于评估 抗miR-33作为CHD的潜在临床治疗。