A hypercholesterolemia-induced immunometabolite in atherosclerosis

高胆固醇血症诱导的动脉粥样硬化免疫代谢物

• 批准号: 10532799
• 负责人: Prediman Krishan Shah
• 金额: $ 61.62万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532799
• 关键词: Arterial Fatty Streak; Atherosclerosis; Attention; Cardiovascular Diseases; Cessation of life; Cholesterol; Chronic; Chronic Disease; Coronary heart disease; DNA Modification Process; Data; Development; Dioxygenases; EIF-2alpha; Endoplasmic Reticulum; Epigenetic Process; Etiology; Eukaryotic Initiation Factors; Family; Genes; Genetic Models; Human; Hyperlipidemia; Hypoxia; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Knock-in; Knowledge; Link; Lipids; Literature; Macrophage; Malignant Neoplasms; Mediating; Mediator; Membrane; Metabolic; Metabolic Pathway; Methylation; Mitochondria; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Myocardial dysfunction; Onset of illness; Organelles; Oxidoreductase; Pathway interactions; Phosphoglycerate dehydrogenase; Phosphorylation; Phosphotransferases; Production; Protein Dephosphorylation; Recovery; Role; Saturated Fatty Acids; Signal Transduction; Signaling Molecule; Somatic Mutation; Sterility; Stimulus; Stress; Stress Response Signaling; Supplementation; Therapeutic; Toxic effect; Translations; Treatment Efficacy; Work; activating transcription factor 1; activating transcription factor 4; alpha ketoglutarate; antagonist; atherogenesis; biological adaptation to stress; cofactor; early onset; endoplasmic reticulum stress; epigenome; genetic approach; hypercholesterolemia; in vivo; insight; new therapeutic target; novel therapeutics; oxidation; prevent; response; small molecule; therapeutic target; transcriptome; vascular inflammation

PROJECT ABSTRACT A maladaptive inflammatory response to lipid imbalance underlies the chronic vascular inflammation in atherosclerosis. Persistent activation of the Integrated Stress Response (ISR) signaling is also observed in both mouse and human atheroma. ISR is an elaborate, homeostatic signaling activated by a range of conditions such as hypoxia, hyperlipidemia and endoplasmic reticulum (ER) and mitochondrial stress, which are known to promote atherosclerosis. Small molecules and genetic models that prevent hypercholesterolemia-induced ISR signaling were shown to prevent atherosclerosis progression, demonstrating ISR’s causality in atherosclerosis development. Despite regulating lipid-induced sterile inflammation, thereby representing a novel therapeutic opportunity in cardiovascular disease (CVD), therapeutic targeting of a homeostatic pathway such as ISR in a chronic disease is not without its challenges. Deciphering the detailed mechanisms by which ISR governs macrophage immunometabolism and atherogenesis can pave the way to effective and specific therapeutic strategies in CVD while escaping toxicity that may be associated with targeting homeostatic signaling. We made the striking discovery that ISR inhibition in hypercholesterolemic mice leads to increased 5- hydroxymethylcytosine (5-hmC) to 5-methylcytosine (5-mC) ratio in macrophages and plaques while reducing IL-1b and atherosclerosis progression. The oxidation of 5-mC to 5-hmC is catalyzed by Ten eleven translocation (TET) family of methylcytosine dioxygenases, somatic mutations in which are associated with coronary heart disease and early-onset myocardial infarction (MI). The inactivation of TET-2 in mice promotes atherosclerosis progression and cardiac dysfunction. Our robust preliminary data shows that hypercholesterolemia induces 2- hydroxyglutarate (2HG), a potent TET inhibitory metabolite, in an ISR-dependent manner. Furthermore, supplementation with a-ketoglutarate (aKG), a cofactor for TET, stimulates TET activity while inhibiting IL-1b secretion in mouse and human macrophages. aKG supplementation in a small group of hypercholesterolemic mice prevented inflammation while reversing TET inhibition. Building on the insight gained through our robust preliminary studies and incorporating additional evidence from literature, we hypothesize that hyperlipidemia- induced ISR signaling generates an immunometabolite that can promote macrophage inflammatory response and atherosclerosis. We propose to investigate ATF4’s role in regulating macrophage immunometabolism and promoting atherosclerosis in vivo. We will also investigate the consequences of modulating 2HG levels in myeloid cells on inflammation and atherosclerosis in hypercholesterolemic mice. The completion of the proposed studies will illuminate the metabolic and epigenetic consequences for ISR signaling in macrophages on sterile inflammation and atherosclerosis development. The new knowledge gained through these studies could pave the way for the development of effective and specific therapeutic strategies to antagonize ISR signaling components that promote sterile inflammation and drive atherosclerosis progression.

项目摘要 对脂质失衡的不良适应性炎症反应是慢性血管炎症的基础 动脉粥样硬化。在两者中也观察到综合应力响应（ISR）信号的持续激活 小鼠和人动脉瘤。 ISR是由一系列条件激活的精心稳态信号传导 如缺氧，高脂血症和内质网（ER）和线粒体应激，已知 促进动脉粥样硬化。小分子和遗传模型，可防止高胆固醇血症诱导的ISR 表明信号传导可防止动脉粥样硬化的进展，表明ISR在动脉粥样硬化中的偶然性 发展。尽管调节脂质诱导的无菌感染，因此代表了一种新的疗法 心血管疾病（CVD）的机会，稳态途径（例如ISR）的治疗靶向 慢性病并非没有挑战。破译ISR管理的详细机制 巨噬细胞免疫代谢和动脉粥样硬化可以为有效和特定的治疗铺平道路 CVD中的策略在逃避毒性时可能与靶向稳态信号有关。我们做了 高胆固醇小鼠ISR抑制的惊人发现导致5-- 在巨噬细胞和斑块中，羟基胞霉素（5-HMC）与5-甲基环胞嘧啶（5-MC）的比率，同时还原 IL-1b和动脉粥样硬化进展。 5-MC至5-HMC的氧化被十11个易位催化 （TET）甲基胞嘧啶二氧酶的家族，体细胞突变与冠状心脏有关 疾病和早期心肌梗塞（MI）。小鼠中TET-2的失活会促进动脉粥样硬化 进展和心脏功能障碍。我们强大的初步数据表明，高胆固醇血症影响2- 羟基戊二酸（2HG），一种潜在的TET抑制代谢物，以ISR依赖性方式。此外， 用A-酮戊二酸（AKG）补充TET的辅助因子（AKG），刺激TET活性，同时抑制IL-1B 小鼠和人类巨噬细胞的分泌。在一小部分高胆固醇中补充AKG 小鼠在逆转TET抑制时阻止了炎症。建立在我们强大的洞察力的基础上 初步研究并纳入了文献中的其他证据，我们假设高脂血症 - 诱导的ISR信号传导会产生一种免疫代谢物，可以促进巨噬细胞炎症 反应和动脉粥样硬化。我们建议研究ATF4在调节巨噬细胞中的作用 免疫代谢和促进体内动脉粥样硬化。我们还将调查 调节髓样细胞的2HG水平在注射和高胆固醇小鼠的动脉粥样硬化时调节。这 拟议研究的完成将阐明ISR信号的代谢和表观遗传后果 在无菌注射和动脉粥样硬化发展的巨噬细胞中。通过 这些研究可能为制定有效和特定的治疗策略铺平道路 拮抗ISR信号传导成分，可促进无菌注射并驱动动脉粥样硬化进展。