Atherosclerosis in SLE - OGG-1 as a novel target for therapeutic intervention

SLE 中的动脉粥样硬化 - OGG-1 作为治疗干预的新靶点

• 批准号: 9306766
• 负责人: Moshe Arditi
• 金额: $ 26.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306766
• 关键词: 8-Oxoguanine DNA Glycosylase; Address; Adopted; Atherosclerosis; Attenuated; Autoimmune Diseases; Binding; Binding Sites; Biological Markers; Cardiovascular system; Cells; Chronic; Cytoplasm; DNA Damage; DNA glycosylase; Data; Development; Disease; Enzymes; Event; General Population; Generations; Genetic Polymorphism; Human; Hyperlipidemia; Immune; Immunologics; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Life; Messenger RNA; MicroRNAs; Mitochondria; Mitochondrial DNA; Mus; Myocardial Infarction; Nephritis; Oxides; Pathogenicity; Patients; Pristane; Process; Production; Reactive Oxygen Species; Risk; Role; Signal Transduction; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; United States; Woman; aged; atherogenesis; cytokine; effective therapy; high risk; mitochondrial dysfunction; monocyte; mortality; mouse model; new therapeutic target; novel; novel therapeutics; oxidative DNA damage; oxidative damage; prevent; protective effect; repaired; therapeutic target; translational approach; unpublished works

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease, which is associated with accelerated atherosclerosis. The overall risk of myocardial infarction (MI) with SLE is 10-fold higher than in the general population and a 50-fold higher risk in women aged 35-44 years. Why patients with SLE or other autoimmune diseases are at increased risk of atherosclerosis remains unclear, and biomarkers are needed to identify those at higher risk of adverse cardiovascular events. Inflammation is a key component of the atherogenic process. Recent studies strongly indicate a central role for the proinflammatory cytokine IL-1β in atherosclerosis, although the mechanism by which IL-1β is activated during atherogenesis is unknown. We have determined that immunologic danger signals induce mitochondrial dysfunction with generation of reactive oxygen species. The resulting oxidatively damaged mitochondrial DNA (mtDNA) is released into the cytoplasm where it binds to and activates the NLRP3 inflammasome, the machinery by which active IL-1β is made. We have shown that 8-oxoguanine-DNA glycosylase 1 (OGG1), an enzyme involved in repairing oxidized mtDNA, prevents NLRP3 inflammasome activation and IL-1β production. Importantly, unpublished work in the Arditi lab demonstrates that mice deficient in OGG1 are more prone to develop atherosclerosis, emphasizing the protective effect of this enzyme. It is well known that SLE patients develop mitochondrial oxidative DNA damage and accumulate very high concentrations of oxidative mtDNA products that in turn amplify inflammation. Moreover, inactivating polymorphisms in OGG1 have been associated with the development of nephritis in SLE. Given this background, we hypothesize that oxidative DNA damage leads to SLE- associated atherogenesis and that OGG1 is protective and hence a novel target for therapeutic intervention. To test this hypothesis, we will adopt a two-pronged approach, using SLE mouse models with hyperlipidemia, and ex vivo analysis of NLRP3 and OGG1 activity and function in immune cells derived from SLE patients with atherosclerosis vs. those without. We propose two Specific Aims: Aim 1-To investigate the role of mitochondrial OGG1 as a novel therapeutic target to prevent SLE-associated atherogenesis. Aim 2 – To determine the role of mtDNA in NLRP3 activation in SLE atherogenesis and the role of OGG1 in limiting mtDNA damage in immune cells from SLE patients with or without atherosclerosis. We will manipulate these systems via mitochondrial targeting of OGG1 or via novel microRNA that regulates OGG1 expression so as to evaluate the utility of targeting OGG1 as a potential therapeutic approach in SLE-associated atherosclerosis. Completion of these studies will significantly enhance our current understanding the pathogenic mechanisms of accelerated atherogenesis during SLE and uncover new therapeutic targets for this very important disease.

系统性红斑狼疮（SLE）是一种慢性炎症性自身免疫性疾病，与 加速动脉粥样硬化。 SLE 患者发生心肌梗死 (MI) 的总体风险比正常人高 10 倍 一般人群中，35-44 岁女性的风险高出 50 倍。为什么患有 SLE 或其他疾病的患者 自身免疫性疾病是否会增加动脉粥样硬化的风险仍不清楚，需要生物标志物来 识别那些心血管不良事件风险较高的人。炎症是炎症的重要组成部分 动脉粥样硬化过程。最近的研究强烈表明促炎细胞因子 IL-1β 在 动脉粥样硬化，尽管在动脉粥样硬化形成过程中 IL-1β 被激活的机制尚不清楚。我们 已经确定免疫危险信号会诱导线粒体功能障碍并产生反应性 氧物种。由此产生的氧化损伤线粒体 DNA (mtDNA) 被释放到细胞质中 它与 NLRP3 炎症小体结合并激活，这是产生活性 IL-1β 的机制。我们 研究表明，8-氧鸟嘌呤-DNA 糖基化酶 1 (OGG1) 是一种参与修复氧化 mtDNA 的酶， 防止 NLRP3 炎性体激活和 IL-1β 产生。重要的是，Arditi 实验室未发表的工作 表明缺乏 OGG1 的小鼠更容易发生动脉粥样硬化，强调 这种酶的保护作用。众所周知，SLE 患者会出现线粒体氧化 DNA 损伤并积累非常高浓度的氧化 mtDNA 产物，进而放大 炎。此外，OGG1 的失活多态性与以下疾病的发生有关： SLE 中的肾炎。鉴于这一背景，我们假设 DNA 氧化损伤会导致 SLE- 相关的动脉粥样硬化形成，OGG1 具有保护作用，因此是治疗的新靶点 干涉。为了验证这一假设，我们将采用双管齐下的方法，使用 SLE 小鼠模型 高脂血症，以及来自来源的免疫细胞中NLRP3和OGG1活性和功能的离体分析 患有动脉粥样硬化的 SLE 患者与没有动脉粥样硬化的患者。我们提出两个具体目标： 目标 1-调查 线粒体 OGG1 作为预防 SLE 相关动脉粥样硬化形成的新治疗靶点的作用。目标 2 – 确定 mtDNA 在 SLE 动脉粥样硬化形成中 NLRP3 激活中的作用以及 OGG1 在限制 患有或不患有动脉粥样硬化的 SLE 患者免疫细胞中 mtDNA 损伤。我们将操纵这些 通过线粒体靶向 OGG1 或通过调节 OGG1 表达的新型 microRNA 系统 评估靶向 OGG1 作为 SLE 相关动脉粥样硬化潜在治疗方法的效用。 这些研究的完成将显着增强我们目前对致病机制的理解 系统性红斑狼疮期间加速动脉粥样硬化的研究，并为这种非常重要的疾病发现新的治疗靶点。

项目成果

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

• DOI: 10.3389/fimmu.2020.554725
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Tumurkhuu G;Chen S;Montano EN;Ercan Laguna D;De Los Santos G;Yu JM;Lane M;Yamashita M;Markman JL;Blanco LP;Kaplan MJ;Shimada K;Crother TR;Ishimori M;Wallace DJ;Jefferies CA;Arditi M
• 通讯作者: Arditi M