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: 10343505
• 负责人: Prediman Krishan Shah
• 金额: $ 69.41万
• 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/10343505
• 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; 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; Malignant Neoplasms; Mediating; Mediator of activation protein; 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; base; biological adaptation to stress; cofactor; early onset; endoplasmic reticulum stress; epigenome; genetic approach; hypercholesterolemia; in vivo; insight; macrophage; 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 对脂质失衡的适应不良炎症反应是慢性血管炎症的基础 动脉粥样硬化。综合应激反应 (ISR) 信号的持续激活也在以下两种情况中观察到： 小鼠和人类动脉粥样硬化。 ISR 是一种复杂的稳态信号传导，由一系列条件激活，例如 如缺氧、高脂血症、内质网 (ER) 和线粒体应激，已知这些因素会导致 促进动脉粥样硬化。预防高胆固醇血症诱导的 ISR 的小分子和遗传模型 信号传导被证明可以预防动脉粥样硬化进展，证明 ISR 在动脉粥样硬化中的因果关系 发展。尽管调节脂质诱导的无菌炎症，从而代表了一种新的治疗方法 心血管疾病（CVD）的机会，稳态途径的治疗目标，例如 ISR 慢性疾病并非没有挑战。破译 ISR 控制的详细机制 巨噬细胞免疫代谢和动脉粥样硬化形成可以为有效和特异性的治疗铺平道路 CVD 策略，同时避免可能与靶向稳态信号相关的毒性。我们做了 令人震惊的发现是，高胆固醇血症小鼠中的 ISR 抑制会导致 5- 巨噬细胞和斑块中羟甲基胞嘧啶 (5-hmC) 与 5-甲基胞嘧啶 (5-mC) 的比率，同时降低 IL-1b 和动脉粥样硬化进展。 10-11易位催化5-mC氧化为5-hmC (TET) 甲基胞嘧啶双加氧酶家族，其体细胞突变与冠心病相关 疾病和早发性心肌梗塞（MI）。小鼠TET-2失活促进动脉粥样硬化 进展和心脏功能障碍。我们强有力的初步数据表明，高胆固醇血症会导致 2- 羟基戊二酸 (2HG) 是一种有效的 TET 抑制代谢物，以 ISR 依赖性方式。此外， 补充 TET 的辅助因子 a-酮戊二酸 (aKG) 可刺激 TET 活性，同时抑制 IL-1b 小鼠和人类巨噬细胞的分泌。一小群高胆固醇血症患者补充 aKG 小鼠预防炎症，同时逆转 TET 抑制。建立在通过我们强大的洞察力获得的洞察力的基础上 初步研究并结合文献中的其他证据，我们假设高脂血症- 诱导的 ISR 信号产生可促进巨噬细胞炎症的免疫代谢物 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 体内免疫代谢和促进动脉粥样硬化。我们也会调查后果 调节骨髓细胞中的 2HG 水平对高胆固醇血症小鼠炎症和动脉粥样硬化的影响。这 拟议研究的完成将阐明 ISR 信号传导的代谢和表观遗传后果 巨噬细胞对无菌性炎症和动脉粥样硬化发展的影响。通过获得的新知识 这些研究可以为制定有效且具体的治疗策略铺平道路 拮抗 ISR 信号成分，促进无菌炎症并推动动脉粥样硬化进展。