A hypercholesterolemia-induced immunometabolite in atherosclerosis

项目摘要 对脂质失衡的不适应性炎症反应是慢性血管炎症的基础。 动脉硬化。整合应激反应(ISR)信号的持续激活也在这两种情况下观察到 老鼠和人类的动脉粥样硬化。ISR是一种精心设计的动态平衡信号，由一系列条件激活，如 如低氧、高脂血症和内质网(ER)以及线粒体应激，这些都是已知的 促进动脉粥样硬化。预防高胆固醇血症诱导的胰岛素抵抗的小分子和遗传模型 信号被证明可以防止动脉粥样硬化的进展，证明了ISR在动脉粥样硬化中的因果关系 发展。尽管调节了脂质诱导的不孕不育炎症，从而代表了一种新的治疗方法 心血管疾病(CVD)的机会，治疗靶向的动态平衡途径，如ISR 慢性病也不是没有挑战。解读ISR治理的详细机制 巨噬细胞的免疫代谢和动脉粥样硬化可以为有效和特异的治疗铺平道路 在CVD中的策略，同时逃避可能与靶向内稳态信号有关的毒性。我们做了 一项令人震惊的发现是，抑制高胆固醇血症小鼠的ISR会导致5-羟色胺的升高 巨噬细胞和斑块中5-羟甲基胞嘧啶(5-HMC)与5-甲基胞嘧啶(5-MC)的比值 IL-1b与动脉粥样硬化进展10个11位易位催化5-MC氧化合成5-羟甲基纤维素 (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死(MI)。小鼠体内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显示，高胆固醇血症导致2- 羟基戊二酸(2HG)，一种有效的Tet抑制代谢物，以ISR依赖的方式。此外， 补充α-酮戊二酸(AKG)，Tet的辅助因子，刺激Tet的活性，同时抑制IL-1b 小鼠和人巨噬细胞的分泌。补充AKG治疗一小部分高胆固醇血症 小鼠在逆转Tet抑制的同时预防炎症。在通过我们的强大的 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信号产生免疫代谢产物，促进巨噬细胞炎症 反应和动脉粥样硬化。我们建议研究血管紧张素转运蛋白4的S在巨噬细胞调节中的作用 体内免疫代谢与促进动脉粥样硬化。我们还将调查 调节髓系细胞2HG水平对高胆固醇血症小鼠炎症和动脉粥样硬化的影响。这个 拟议研究的完成将阐明ISR信号的代谢和表观遗传后果 巨噬细胞对无菌炎症和动脉粥样硬化发展的影响。通过新知识获得的 这些研究可以为制定有效和具体的治疗策略铺平道路。 拮抗促进无菌炎症和推动动脉粥样硬化进展的ISR信号成分。

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.