Pathological flow-induced endothelial damage and plaque erosion

病理性血流诱导的内皮损伤和斑块侵蚀

• 批准号: 9974575
• 负责人: Jun-Ichi Abe
• 金额: $ 79.39万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974575
• 关键词: Affect; Animal Model; Apoptosis; Area; Arterial Fatty Streak; Binding; Blood flow; Cell Aging; Cell Proliferation; Chemicals; Complex; Data; Development; Edema; Endothelial Cells; Endothelium; Event; Feedback; Fibrin; Fibrinogen; Functional disorder; Goals; Hemorrhage; High Fat Diet; Homologous Gene; In Vitro; Inflammation; Injections; Knock-in Mouse; Knock-out; LATS1 gene; Lasers; Lesion; Link; MAPK7 gene; Mechanics; Mediating; Molecular; Mus; Necrosis; Outcome; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Proteins; Research; Role; Rupture; Signal Pathway; Signal Transduction; Sudden Death; TERF2 gene; Tamoxifen; Testing; Thromboplastin; Thrombus; Time; Tumor Suppressor Proteins; Work; aortic arch; atherosclerosis risk; base; cell injury; coronary event; high risk; hypercholesterolemia; innovation; insight; novel strategies; novel therapeutic intervention; prevent; protein degradation; senescence; shear stress; telomere; theories; transcription factor; ubiquitin-protein ligase

Project Summary/Abstract Atherosclerotic and high-risk plaques including both rupture and erosion are predominantly localized to vessel wall regions with non-laminar disturbed blood flow (d-flow) and laminar high flow (h-flow). However, the molecular mechanisms of this pathological flow-induced high-risk plaque remain largely unknown mainly because of the lack of such high-risk plaque animal models, hence there is an urgent need to correct this gap. Our long-term goal is to determine how the high-risk plaque is formed by pathological flow. We found that within 14 days after inducing LATS (large tumor suppressor homolog) 1/2 deletion in tamoxifen-inducible endothelial cell (EC) specific LATS1homo/LATS2homoknock-out mice (LATS1homo/LATS2homo-EKO), all mice (28/28) died of severe systemic edema, accompanied by massive EC apoptosis. Next we generated EC- specific LATS1het/LATS2homo-EKO hypercholesteremic (H-chol) mice; we detected a plaque erosion-like lesions at h- and d-flow areas in the aortic arch and carotids, which revealed strong fibrin/fibrinogen positive organized thrombus formation without a large necrotic core. We observed significant increases in 1) EC proliferation, 2) EC apoptosis with senescent phenotype, 3) tissue factor (TF) expression, and 4) inflammation, which are collectively referred to as the “pro-thrombotic phenotype”. We hypothesize that pathological flow-induced LATS1/2 degradation promotes EC damage-mediated thrombus formation and luminal re-endothelialization in concert. This cycle of EC damage-thrombus-re-endothelialization results in largethrombus formation and plaque erosion. Pathological flow-induced MAGI1 S741 phosphorylation by PKC, and the subsequent LATS1/2-TERF2IP-MKRN1 complex formation are essential for LATS1/2 degradation. To test ths hypothesis, we propose the following 3 aims. In aim 1, we will characterize the role of excess EC proliferation, senescence/apoptosis, tissue factor (TF) expression, and inflammation in the formation of plaque erosion-like lesions and intraplaque hemorrhage in EC specific Lats1het/Lats2homo knock-out (Lats1het/Lats2homo-EKO) mice under H-chol. In aim 2, we will determine the crucial role of phosphorylation dependent TERF2IP and MKRN1 Ub E3 ligase binding in pathological flow-induced LATS1/2 destabilization and the consequent pro-thrombotic phenotype, and in aim 3 we will Investigate the role of PKC-induced MAGI1 S741 phosphorylation in LATS1/2-mediated TERF2IP S205 phosphorylation and LATS1/2 degradation. The proposed work is expected to establish the link between pathological flow and pro-thrombotic phenotype, by which high-risk plaques are formed. The proposed study is innovative because it will propose a new concept how pathological flow affects the endothelium and induce the formation of vulnerable plaques of erosion and will provide insights into new signaling cascades and molecules responsible for this pathology. The proposed research may also provide means to predict and prevent high-risk plaque formation.

项目摘要/摘要 包括破裂和侵蚀在内的动脉粥样硬化和高风险斑块主要局限于血管 具有非晶状体干扰血流（D-Flow）和层流高流量（H-Flow）的壁区。但是， 这种病理流动引起的高风险斑块的分子机制主要未知 由于缺乏如此高风险的斑块动物模型，因此迫切需要纠正这一差距。 我们的长期目标是确定如何通过病理流动形成高风险牌匾。我们发现 在诱导LATS（大肿瘤抑制剂同源物）1/2缺失后14天内 内皮细胞（EC）特定的LATS1HOMO/LATS2HOMOKNOCK-OUT小鼠（LATS1HOMO/LATS2HOMO-EKO），所有小鼠 （28/28）死于严重的全身水肿，通过​​大量EC凋亡完成。接下来，我们产生了 特定的LATS1HET/LATS2HOMO-EKO高胆固醇（H-Chol）小鼠；我们检测到牙菌斑状的病变 在主动脉弓和颈动脉中的H和D流动区域，揭示了强烈的纤维蛋白/纤维蛋白原积极组织 血栓形成没有大坏死核。我们观察到1）EC增殖的显着增加，2） 具有感觉表型的EC凋亡，3）组织因子（TF）表达和4）炎症，这是 统称为“亲栓性表型”。我们假设病理流动诱导 LATS1/2降解促进了EC损伤介导的血栓形成和腔内皮层化。 音乐会。 EC损伤 - 肉瘤 - 重新皮层化的这一周期导致形成大量的甲基曲霉和 斑块侵蚀。病理流动诱导的MAGI1 S741磷酸化，随后的 LATS1/2-TERF2IP-MKRN1复合物形成对于LATS1/2降解至关重要。为了检验假设， 我们提出以下3个目标。在AIM 1中，我们将表征超过EC增殖的作用， 在形成斑块样形成中的感应/凋亡，组织因子（TF）表达和炎症 EC特异性LATS1HET/LATS2HOMO敲除（LATS1HET/LATS2HOMO-EKO）小鼠的病变和内部出血 在H-Chol下。在AIM 2中，我们将确定磷酸化依赖性TERF2IP和MKRN1的关键作用 病理流动诱导的LATS1/2不稳定的UB E3连接酶结合，随之而来的促脉症 表型，在AIM 3中，我们将研究PKC诱导的MAGI1 S741磷酸化在 LATS1/2介导的TERF2IP S205光态和LATS1/2降解。预计拟议的工作 为了建立病理流动与促栓性表型之间的联系，高风险斑块是 形成。拟议的研究具有创新性，因为它将提出一个新的概念病理流动如何影响 内皮并诱导脆弱的侵蚀颗粒的形成，并将提供新的见解 负责该病理的信号传导级联反应和分子。拟议的研究也可能提供 预测和预防高风险斑块形成的手段。