RNA-Mediated Inter-Organelle Communication in Atherosclerosis

RNA介导的动脉粥样硬化细胞器间通讯

• 批准号: 10630220
• 负责人: Moshe Arditi
• 金额: $ 49.89万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630220
• 关键词: Ablation; Affect; Arterial Fatty Streak; Arteries; Atherosclerosis; Automobile Driving; Binding; Biogenesis; Cardiovascular Diseases; Cells; Chromosome 2; Chronic; Communication; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endoplasmic Reticulum; Endoribonucleases; Enzymes; Epidemic; High Density Lipoproteins; Human Chromosomes; Hyperlipidemia; Immune; Impairment; Inflammation; Inflammatory; Inositol; Insulin Resistance; Ischemia; Link; Lipids; Literature; Macrophage; Mediating; Membrane; Metabolic; MicroRNAs; Mitochondria; Molecular; Mus; Mutate; Nutrient; Obesity; Organelles; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasma; Play; Proteins; RNA; RNA Processing; RNA-Binding Proteins; RNA-Induced Silencing Complex; Regulation; Reporting; Ribonucleases; Role; Signal Transduction; Site; Sterility; Stress; Substrate Specificity; Therapeutic; Transcription Factor AP-1; Work; atherogenesis; ds RNA-Binding Proteins; endonuclease; endoplasmic reticulum stress; immune activation; in vivo; insight; locked nucleic acid; novel; novel therapeutic intervention; novel therapeutics; operation; premature; protein kinase R; sensor; small molecule inhibitor; therapeutic target; thrombotic

PROJECT ABSTRACT Ischemic cardiovascular disease (CVD) is caused by atherosclerosis, a lipid-driven inflammatory disease affecting the arteries, which can progress into vulnerable plaques and thrombotic occlusion. The precise molecular mechanisms linking nutrient excess and hyperlipidemia to immune activation remains elusive and the discovery of these mechanisms could lead to novel CVD therapeutics. An important primer for inflammation in dyslipidemia is the chronic metabolic overloading and impairment of anabolic and catabolic organelles. Reduction of organelle stress alleviates insulin resistance and atherosclerosis. Recently, we showed that small molecule inhibitors of Inositol-requiring enzyme -1 (IRE1), a proximal ER stress sensor, counteract atherosclerosis progression. The ER membranes also serve as a nucleation site for RNA-induced silencing complex (RISC), and we made the striking discovery that IRE1 kinase phosphorylates the double stranded RNA-binding protein, the protein activator of the protein kinase R (PACT), that associates with RISC. We found lipid stress induces IRE1 to phosphorylate PACT, which suppresses mitochondrial biogenesis (mito-biogenesis), in part by controlling a miRNA (miR)-181c. Homeostatic mechanisms such as mitophagy (to remove) or mito-biogenesis (to replenish) the malfunctioning mitochondria can counteract inflammation and also operate in atherosclerotic plaque cells. Aberrant activation of IRE1-PACT signaling by lipids block mito-biogenesis and propagate mitochondrial oxidative (MOX) stress and inflammation, indicating inhibition of this pathological signaling could counteract atherosclerosis. PACT is proximal to a locus on human chromosome 2 that is linked to premature coronary artery disease and plasma HDL-C levels. PACT expression is induced during atherosclerosis progression and reduced during regression in mice. We hypothesize that suppressing IRE1-PACT signaling will promote mito-biogenesis and counteract inflammation and atherosclerosis. We will elucidate how PACT regulates mito-biogenesis by discovering PACT’s miR target(s) and their RNA targets that are relevant to mito-biogenesis regulation. We discovered miR-181c is one of these PACT targets that blocks mito-biogenesis. We will directly investigate the impact of PACT and miR-181c on hyperlipidemia-induced mito-biogenesis, inflammation and atherosclerosis in vivo. Based on the discovered targets (for miR-181c and others) we will develop a more specific therapeutic targeting approach (using Locked Nucleic Acid-Target-Site Blockers) to ablate miR and target interaction in atherosclerotic mice. The successful completion of these studies will help define an unprecedented mechanism of immune-metabolic crosstalk between ER and mitochondria by which hyperlipidemia can promote MOX stress, inflammation and atherosclerosis. Understanding the intrinsic operation of this RNA-mediated inter-organelle communication during atherogenesis could pave the way for novel therapeutic approaches targeting this specific immune-metabolic cross talk in CVD.

项目摘要 缺血性心血管疾病 (CVD) 是由动脉粥样硬化引起的，动脉粥样硬化是一种脂质驱动的炎症性疾病 影响动脉，可能发展成易损斑块和血栓闭塞。精确的 将营养过剩和高脂血症与免疫激活联系起来的分子机制仍然难以捉摸 这些机制的发现可能会带来新的心血管疾病治疗方法。重要的入门读物 血脂异常中的炎症是慢性代谢超负荷以及合成代谢和代谢障碍 分解代谢细胞器。减少细胞器应激可减轻胰岛素抵抗和动脉粥样硬化。 最近，我们发现肌醇需求酶 -1 (IRE1) 的小分子抑制剂，一种近端 ER 压力传感器，抵消动脉粥样硬化的进展。 ER 膜也可作为成核位点 对于 RNA 诱导的沉默复合物 (RISC)，我们做出了惊人的发现，IRE1 激酶 磷酸化双链 RNA 结合蛋白，即蛋白激酶 R 的蛋白激活剂 (PACT)，与 RISC 相关。我们发现脂质应激会诱导 IRE1 磷酸化 PACT，从而 部分通过控制 miRNA (miR)-181c 来抑制线粒体生物发生 (mito-biogenesis)。 稳态机制，例如线粒体自噬（以消除）或有丝分裂生物发生（以补充）故障 线粒体可以对抗炎症，也可以在动脉粥样硬化斑块细胞中发挥作用。异常激活 脂质对 IRE1-PACT 信号传导的影响阻断线粒体生物发生并传播线粒体氧化 (MOX) 应激 和炎症，表明抑制这种病理信号可以对抗动脉粥样硬化。协议 靠近人类 2 号染色体上的一个位点，该位点与过早冠状动脉疾病有关，并且 血浆 HDL-C 水平。 PACT 表达在动脉粥样硬化进展期间被诱导，并在动脉粥样硬化进展期间减少。 小鼠的回归。我们假设抑制 IRE1-PACT 信号传导将促进有丝分裂生物发生 并对抗炎症和动脉粥样硬化。我们将通过以下方式阐明 PACT 如何调节有丝分裂生物发生： 发现 PACT 的 miR 靶点及其与有丝分裂生物发生调控相关的 RNA 靶点。我们 发现 miR-181c 是阻断有丝分裂生物发生的 PACT 靶标之一。我们将直接调查 PACT 和 miR-181c 对高脂血症诱导的有丝分裂生物发生、炎症和动脉粥样硬化的影响 体内。基于发现的靶标（针对 miR-181c 和其他靶标），我们将开发更具体的 治疗靶向方法（使用锁定核酸靶点阻断剂）消除 miR 并靶向 动脉粥样硬化小鼠中的相互作用。这些研究的成功完成将有助于确定 内质网和线粒体之间前所未有的免疫代谢串扰机制 高脂血症可促进MOX应激、炎症和动脉粥样硬化。了解内在 这种 RNA 介导的细胞器间通讯在动脉粥样硬化形成过程中的运作可能为动脉粥样硬化形成铺平道路。 针对 CVD 中这种特定免疫代谢串扰的新治疗方法的方法。

项目成果

PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c.

• DOI: 10.1016/j.jbc.2022.102050
• 发表时间: 2022-07
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Dogan, Asli E.;Hamid, Syed M.;Yildirim, Asli D.;Yildirim, Zehra;Sen, Ganes;Riera, Celine E.;Gottlieb, Roberta A.;Erbay, Ebru
• 通讯作者: Erbay, Ebru