A hypercholesterolemia-induced immunometabolite in atherosclerosis

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， 动脉粥样硬化在这两种细胞中也观察到整合应激反应（ISR）信号的持续激活。 小鼠和人类动脉粥样化。ISR是一种复杂的稳态信号，由一系列条件激活， 如缺氧、高脂血症、内质网（ER）和线粒体应激，已知它们 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阻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 发展尽管调节脂质诱导的无菌性炎症，从而代表了一种新的治疗方法， 在心血管疾病（CVD）中的机会，治疗靶向稳态途径，如ISR， 慢性病并非没有挑战。解析ISR管理的详细机制 巨噬细胞的免疫代谢和动脉粥样硬化的形成可以为有效和特异性的治疗铺平道路 在CVD中的策略，同时逃避可能与靶向稳态信号相关的毒性。我们做 令人震惊的发现是，高胆固醇血症小鼠中ISR抑制导致5- 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与动脉粥样硬化进展5-mC氧化为5-hmC是由10 - 11易位催化的 (TET)甲基胞嘧啶双加氧酶家族，与冠心病相关的体细胞突变 疾病和早发性心肌梗死（MI）。小鼠体内泰特-2的失活促进动脉粥样硬化 进展和心功能障碍。我们可靠的初步数据表明，高胆固醇血症诱导2- 羟基戊二酸（2 HG），一种有效的泰特抑制代谢物，以ISR依赖性方式。此外，委员会认为， 补充泰特辅因子α-酮戊二酸（aKG）可刺激泰特活性，同时抑制IL-1 b 小鼠和人巨噬细胞中的分泌。在一小组高胆固醇血症患者中补充aKG 小鼠在逆转泰特抑制的同时预防炎症。基于我们通过强大的 通过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信号产生免疫代谢物，可促进巨噬细胞炎症 反应和动脉粥样硬化。我们建议研究ATF 4在调节巨噬细胞 免疫代谢和促进体内动脉粥样硬化。我们还将调查 在高胆固醇血症小鼠中调节髓样细胞中的2 HG水平对炎症和动脉粥样硬化的影响。的 这些研究的完成将阐明ISR信号传导的代谢和表观遗传后果 在巨噬细胞无菌炎症和动脉粥样硬化的发展。通过以下方式获得的新知识 这些研究可以为开发有效和特异性的治疗策略铺平道路， 拮抗促进无菌炎症和驱动动脉粥样硬化进展的ISR信号传导组分。

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.