Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections

散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡

• 批准号: 10239058
• 负责人: SCOTT A LEMAIRE
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239058
• 关键词: Angiotensin II; Aorta; Aortic Diseases; Apoptotic; Area; Attention; Biomechanics; Cardiovascular Diseases; Cause of Death; Cell Death; Cell membrane; Cells; Cellular Stress; Cessation of life; Clinical; Coupled; Cyclic GMP; Cytosol; DNA; Development; Dilatation - action; Disease; Disease Progression; Dissection; Electron Microscopy; Extracellular Matrix; Failure; Genetic Diseases; Goals; High Fat Diet; Inflammation; Inflammatory; Infusion procedures; Knock-out; Knockout Mice; Life; Lytic; Marfan Syndrome; Mediating; Membrane; Mission; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Necrosis; Nonlytic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Prevention; Process; Protein Kinase; Public Health; RIPK1 gene; RIPK3 gene; Reaction; Reactive Oxygen Species; Research; Role; Rupture; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stimulator of Interferon Genes; Swelling; TANK-binding kinase 1; TBK1 gene; Testing; Thoracic Aortic Aneurysm; Tissues; Trauma; United States; aged; ascending aorta; cell injury; cell type; experimental study; improved; inhibitor/antagonist; insight; mouse model; novel; prevent; sensor; therapeutic evaluation; therapeutic target

Project Summary/Abstract (30 lines) Ascending thoracic aortic aneurysms and dissections (ATAAD) are extremely lethal surgical diseases. ATAAD occurs either in association with genetic conditions or spontaneously as sporadic ATAAD, which accounts for more than 80% of ATAAD. Unfortunately, no clinically proven medication is available to prevent sporadic ATAAD progression. There is a critical need to develop effective pharmacological strategies to treat these diseases. This project focuses on sporadic ATAAD. One of the significant features of sporadic ATAAD is progressive smooth muscle cell (SMC) depletion, for which the underlying mechanisms are poorly understood. Necrotic cell death, a type of cell death characterized by cell swelling and membrane rupture, causes the release of “toxic” molecules from dying cells, leading to further damage of surrounding cells and extracellular matrix and a profound pro-inflammatory reaction. Necrotic cell death is regulated by a programmed process called necroptosis. Mitochondrial damage, often observed in aged or stressed cells, is a potent trigger for necrotic cell death. The overall objective of this application is to determine the role of mitochondrial damage and SMC necroptosis in the development of TAAD; and the extent to which this mechanism represents a therapeutic target against ATAAD. Our central hypotheses are: (1) mitochondrial damage and subsequent release of mtDNA trigger the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which activates the RIP3-MLKL pathway and induces SMC necroptosis, contributing to aortic damage and ATAAD formation; and (2) reducing mitochondrial damage or inhibiting SMC necroptosis will prevent aortic destruction and ATAAD progression. We will test these hypotheses via 3 aims. Aim 1. We will test the hypothesis that mitochondrial damage and subsequent release of mtDNA activates the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which in turn activates the RIP3-MLKL necroptosis pathway, leading to SMC necrotic death. We will perform serial experiments in cultured SMCs to dissect the signaling leading to necrotic cell death (Aim 1B); and evaluate SMC mitochondrial damage and necrotic cell death in patient tissues by electron microscopy analysis (Aim 1B). Aim 2. We will test the hypothesis that cGAS and RIP3-mediated SMC necroptosis are critically involved in aortic SMC injury, aortic destruction, inflammation, biomechanical failure, and ATAAD development by comparing these aspects in WT mice, cGas-/- mice, Rip3-/- mice, and SMC specific Rip3 knockout mice in a sporadic ATAAD model induced by HFD/Ang II challenge. Aim 3. We will test the hypothesis that pharmacologically reducing mitochondrial damage or necroptosis will prevent aortic destruction and disease progression in our sporadic ATAAD mouse model. The proposed research is significant because it will not only provide novel insight of the molecular mechanisms of sporadic ATAAD development, but also test new treatments for preventing sporadic ATAAD formation and its fatal sequelae. The novel mechanisms of mitochondrial damage-induced SMC necroptosis will also have broad implications in many other cardiovascular diseases.

项目摘要/摘要(30行) 升主动脉瘤和夹层(ATAAD)是一种极其致命的外科疾病。ATAAD 要么与遗传条件有关，要么自发为散发性ATAAD，这解释了 超过80%的ATAAD。不幸的是，没有临床证明的药物可以防止零星的 ATAAD进展。迫切需要开发有效的药理学策略来治疗这些疾病。该项目的重点是零星的ATAAD。散发性ATAAD的一个重要特征是进行性平滑肌细胞(SMC)耗竭，其潜在机制尚不清楚。坏死性细胞死亡是一种以细胞肿胀和细胞膜破裂为特征的细胞死亡，导致死亡细胞释放有毒分子，导致周围细胞和细胞外基质进一步损伤，并发生深刻的促炎反应。坏死性细胞死亡由一个程序化的过程调节，称为 坏死性下垂。线粒体损伤，常见于衰老或应激状态的细胞，是导致坏死性病变的重要诱因。 细胞死亡。这项应用的总体目标是确定线粒体损伤和SMC的作用 TAAD发展过程中的坏死性下垂；以及这一机制在多大程度上代表了ATAAD的治疗靶点。我们的中心假设是：(1)线粒体损伤和随后mtDNA的释放 激活胞浆DNA传感器cGAS-STING-TBK1信号通路，激活RIP3-MLKL通路，诱导SMC坏死性下垂，促进主动脉损伤和ATAAD的形成；(2)减少线粒体损伤或抑制SMC坏死性下垂将防止主动脉破坏和ATAAD的进展。我们 我将通过3个目标来检验这些假设。目的1.我们将验证线粒体损伤和随后mtDNA的释放激活胞质DNA传感器cGAS-STING-TBK1信号通路的假设，该信号通路在 TURN激活RIP3-MLKL坏死性下垂通路，导致SMC坏死性死亡。我们将在培养的SMC中进行一系列实验，以剖析导致坏死性细胞死亡的信号(目标1B)；并评估SMC 通过电子显微镜分析患者组织中的线粒体损伤和坏死性细胞死亡(目标1B)。目标 2.我们将验证cGAS和RIP3介导的SMC坏死性下垂与主动脉病变密切相关的假设 SMC损伤、主动脉破坏、炎症、生物力学衰竭和ATAAD发生的比较 在WT小鼠、cGAS-/-小鼠、RIP3-/-小鼠和SMC特异性RIP3基因敲除小鼠中的这些方面 HFD/Ang II诱导的ATAAD模型。目的3.在我们的散发性ATAAD小鼠模型中，我们将测试药物减少线粒体损伤或坏死性下垂将防止主动脉破坏和疾病进展的假设。这项拟议的研究具有重要意义，因为它不仅提供了新的见解 研究散发性ATAAD发生的分子机制，同时也测试新的预防方法 散发性ATAAD形成及其致命后遗症。线粒体损伤的新机制 SMC坏死性下垂对许多其他心血管疾病也有广泛的影响。

项目成果

Early Detection of Aortic Degeneration in a Mouse Model of Sporadic Aortic Aneurysm and Dissection Using Nanoparticle Contrast-Enhanced Computed Tomography.

• DOI: 10.1161/atvbaha.120.315210
• 发表时间: 2021-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Ghaghada KB;Ren P;Devkota L;Starosolski Z;Zhang C;Vela D;Stupin IV;Tanifum EA;Annapragada AV;Shen YH;LeMaire SA
• 通讯作者: LeMaire SA

New Technologies With Increased Precision Improve Understanding of Endothelial Cell Heterogeneity in Cardiovascular Health and Disease.

• DOI: 10.3389/fcell.2021.679995
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Dawson A;Wang Y;Li Y;LeMaire SA;Shen YH
• 通讯作者: Shen YH

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

• DOI: 10.1038/s41591-020-1133-8
• 发表时间: 2021-01
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Park J;Lucas AM;Zhang X;Chaudhary K;Cho JH;Nadkarni G;Dobbyn A;Chittoor G;Josyula NS;Katz N;Breeyear JH;Ahmadmehrabi S;Drivas TG;Chavali VRM;Fasolino M;Sawada H;Daugherty A;Li Y;Zhang C;Bradford Y;Weaver J;Verma A;Judy RL;Kember RL;Overton JD;Reid JG;Ferreira MAR;Li AH;Baras A;LeMaire SA;Shen YH;Naji A;Kaestner KH;Vahedi G;Edwards TL;Chen J;Damrauer SM;Justice AE;Do R;Ritchie MD;Rader DJ
• 通讯作者: Rader DJ

AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.

在静脉血栓形成小鼠模型中，AKT2 调节内皮介导的凝血稳态并促进血栓内再通和血栓溶解。

• DOI: 10.1007/s11239-020-02112-9
• 发表时间: 2020
• 期刊: Journal of thrombosis and thrombolysis
• 影响因子: 4
• 作者: Xie,Wanmu;Zhang,Lin;Luo,Wei;Zhai,Zhenguo;Wang,Chen;Shen,YingH
• 通讯作者: Shen,YingH