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

基本信息

批准号：
10201742
负责人：
Jun-Ichi Abe
金额：
$ 78.83万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10201742
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 thrombotic transcription factor ubiquitin-protein ligase

项目摘要

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.

项目概要/摘要动脉粥样硬化和高风险斑块（包括破裂和糜烂）主要局限于血管具有非层流扰动血流（d 流）和层流高血流（h 流）的壁区域。这种病理性血流引起的高风险斑块的分子机制仍然很大程度上未知由于缺乏此类高危斑块动物模型，因此迫切需要纠正这一空白。我们的长期目标是确定高风险斑块是如何通过病理流动形成的。在他莫昔芬诱导剂中诱导 LATS（大肿瘤抑制同源物）1/2 缺失后 14 天内内皮细胞 (EC) 特异性 LATS1homo/LATS2homoknock-out 小鼠 (LATS1homo/LATS2homo-EKO)，所有小鼠 (28/28) 死于严重的全身水肿，并伴有大量 EC 凋亡接下来我们生成了 EC-。特定的 LATS1het/LATS2homo-EKO 高胆固醇 (H-chol) 小鼠检测到斑块糜烂样病变；在主动脉弓和颈动脉的 h 和 d 流区域，显示出强纤维蛋白/纤维蛋白原阳性组织我们观察到 1) EC 增殖显着增加，2) 没有大的坏死核心。具有衰老表型的 EC 凋亡、3) 组织因子 (TF) 表达和 4) 炎症，这些是我们捕获了病理性血流诱导的现象，统称为“促血栓表型”。 LATS1/2 降解促进 EC 损伤介导的血栓形成和管腔再内皮化 EC损伤-血栓-再内皮化的这个循环导致大血栓形成和。 PKC 引起的病理性流诱导 MAGI1 S741 磷酸化，以及随后的情况。 LATS1/2-TERF2IP-MKRN1 复合物的形成对于 LATS1/2 降解至关重要。我们提出以下 3 个目标在目标 1 中，我们将描述 EC 过度扩散的作用，衰老/凋亡、组织因子（TF）表达以及斑块侵蚀样形成中的炎症 EC 特异性 Lats1het/Lats2homo 敲除 (Lats1het/Lats2homo-EKO) 小鼠中的病变和斑块内出血在 H-chol 下，在目标 2 中，我们将确定磷酸化依赖性 TERF2IP 和 MKRN1 的关键作用。 Ub E3 连接酶在病理流诱导的 LATS1/2 不稳定中的结合以及随后的促血栓形成表型，在目标 3 中，我们将研究 PKC 诱导的 MAGI1 S741 磷酸化在 LATS1/2 介导的 TERF2IP S205 磷酸化和 LATS1/2 降解预计将开展工作。建立病理血流和促血栓表型之间的联系，通过这种联系高风险斑块所提出的研究具有创新性，因为它将提出病理流如何影响的新概念。内皮细胞并诱导易损侵蚀斑块的形成，并将提供新的见解拟议的研究还可能提供导致这种病理学的信号级联和分子。意味着预测和预防高风险斑块形成。