Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension

既定高血压中的基质相互作用分子 1、免疫细胞和血管病理学

• 批准号: 10206263
• 负责人: KHALID MATROUGUI
• 金额: $ 37.5万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206263
• 关键词: Address; Adverse event; Angiotensins; Anti-Inflammatory Agents; Apoptosis; Biological; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Count; Cell Death; Cell membrane; Cell physiology; Cells; Chimera organism; Clinical; Clip; Complication; Cytokine Signaling; Data; Dendritic Cells; Dendritic cell activation; Development; Endoplasmic Reticulum; Endothelial Cells; Female; Fibrosis; Generations; Genotype; Goals; Hypertension; IL2RA gene; Immune; Immune system; Inflammation; Inflammatory; Infusion procedures; Interferon Type II; Interleukin-1 beta; Kidney; Knockout Mice; Mediator of activation protein; Menopause; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Outcome; Ovariectomy; Pathologic Processes; Pathology; Patients; Preventive; Proteins; Public Health; Regulatory T-Lymphocyte; Reporting; Research Priority; STIM1 gene; Ships; Signal Transduction; Strategic Planning; Structure; T-Lymphocyte; Tail; Testing; Therapeutic; Translational Research; Translations; Vascular Diseases; Vascular Endothelium; Vascular System; base; calcification; cardiovascular risk factor; clinically significant; cytokine; design; endoplasmic reticulum stress; endothelial dysfunction; gene therapy; high risk; improved; male; mortality; mouse model; multidisciplinary; novel therapeutics; overexpression; prevent; therapy resistant

ABSTRACT — The central mechanisms involved in hypertension-induced vascular pathology, a public health crisis, remain unknown. There is still a significant rate of adverse events in hypertensive patients prescribed these therapeutic and 2/3 of hypertensive patients are still resistant to these therapies. Thus, the critical unmet need is to identify mechanism based-treatable targets to rescue vascular function and structure in established hypertension. The pilot data showed that transferring healthy Treg into a mouse with established hypertension-induced by angiotensin II (Ang II) infusion improved vascular endothelial function and structure. We showed an increase in stromal interaction molecule 1 (STIM1) expression in Treg that could be responsible for Treg apoptosis by Nox2 and endoplasmic reticulum (ER) stress- dependent mechanisms. The overexpression of STIM1 in Treg cell caused Treg cell apoptosis. The depletion of dendritic cells in hypertensive mice improved arterial function and reduced arterial fibrosis and calcification through a reduction in INFγ and IL-1β release from dendritic cells and the inhibition of the ER stress in the endothelial cells. The central hypothesis is that STIM1 overexpression in Treg cells, through ROS and ER stress mechanism, cause Treg cells apoptosis and decrease IL-10 release, which increases dendritic cell activity leading to an increase in pro-inflammatory cytokines release (INFγ and IL-1β) and a decrease in anti-inflammatory IL-10 release causing the induction of the ER stress in endothelial cells and vascular pathology. To advance the Translational Sciences, we will test the hypothesis in two-kidney one- clip (2K1C) hypertensive mice Ang II-dependent. Specific Aim #1: To determine that in established hypertension, STIM1 expression is increased in Treg cells causing Treg cells apoptosis, a decrease in IL-10 release, and vascular pathology. Thus disrupting STIM1 expression in Treg cells would restore Treg cells number, IL-10 levels, and improve vascular endothelial function and reduce fibrosis and calcification in established hypertension. Specific Aim #2: To delineate that the decrease in IL-10 release, because of apoptosis in Treg, increases dendritic cells activity to release IFNγ and IL-1β and blunt IL-10 release, which causes vascular pathology via the induction of the ER stress mechanism in endothelial cells, and therefore depleting dendritic cells or manipulating the ER stress in endothelial cell improve vascular endothelial function and reduce fibrosis and calcification in established hypertension-induced by 2K1C. These studies are central to the mission of the NHLBI and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies will address 1) a need to further illuminate the biological mechanisms and pathological processes of the contribution of the immune cells, 2) The interaction between the immune system and the vascular system as a priority research topic and, 3) To advance the Translational Sciences, we will test the hypothesis in 2K1C mice model.

摘要-公众认为高血压诱导的血管病理学涉及的核心机制 健康危机，仍然未知。高血压患者的不良事件发生率仍然很高 这些治疗和2/3的高血压患者仍然耐药这些治疗。因此，在本发明中， 关键的未满足的需求是确定基于机制的可治疗靶点以挽救血管功能， 高血压的结构。试验数据显示，将健康的Treg转移到小鼠体内， 血管紧张素II（Ang II）输注诱导的高血压患者， 功能和结构。我们发现，在高分化的乳腺癌中，基质相互作用分子1（STIM 1）的表达增加。 Treg可能通过Nox 2和内质网（ER）应激导致Treg凋亡- 依赖机制。STIM 1在Treg细胞中的过表达可导致Treg细胞凋亡。的 高血压小鼠中树突状细胞的耗竭改善了动脉功能并减少了动脉纤维化， 通过减少树突状细胞释放的INFγ和IL-1β以及抑制ER 内皮细胞的压力。中心假设是，STIM 1在Treg细胞中的过表达，通过 ROS和ER应激机制导致Treg细胞凋亡并减少IL-10的释放， 树突状细胞活性导致促炎细胞因子释放（INFγ和IL-1β）增加， 抗炎性IL-10释放的减少导致内皮细胞中ER应激的诱导， 血管病理学为了推进转化科学，我们将在两肾一肾中测试这一假设- 夹子（2K 1C）高血压小鼠血管紧张素II依赖性。具体目标#1：确定在建立 高血压时，Treg细胞中STIM 1表达增加，导致Treg细胞凋亡，IL-10表达减少， 释放和血管病理学。因此，破坏Treg细胞中的STIM 1表达将恢复Treg细胞 数量，IL-10水平，并改善血管内皮功能，减少纤维化和钙化， 确诊高血压。具体目标#2：描述由于以下原因导致的IL-10释放减少： Treg中的细胞凋亡，增加树突状细胞释放IFNγ和IL-1β的活性，并抑制IL-10的释放， 通过诱导内皮细胞中的ER应激机制引起血管病理学，因此 去除树突状细胞或操纵内皮细胞中的ER应激可以改善血管内皮细胞的功能。 在2K 1C诱导的高血压中发挥作用并减少纤维化和钙化。这些研究 是《国家HLBI》使命的核心，涉及《国家HLBI》中概述的所有目标和多项战略 战略计划。这些研究将解决1）需要进一步阐明生物学机制， 免疫细胞的贡献的病理过程，2）免疫细胞之间的相互作用， 系统和血管系统作为优先研究课题，3）推进转化科学， 我们将在2K 1C小鼠模型中检验这一假设。