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: 10673211
• 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/10673211
• 关键词: Address; Adverse event; Angiotensin II; Anti-Inflammatory Agents; Apoptosis; Biological; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Count; Cell Death; Cell membrane; Cell physiology; Cells; Chimera organism; Clinical; Clip; Complication; 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; Interleukin-10; Kidney; Knockout Mice; Mediator; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Outcome; Pathologic Processes; Pathology; Patients; Postmenopause; Preventive; Proteins; Public Health; Regulatory T-Lymphocyte; Reporting; Research Priority; STIM1 gene; Signal Transduction; Strategic Planning; Structure; T-Lymphocyte; Tail; Testing; Therapeutic; Translational Research; Translations; Vascular Diseases; Vascular Endothelium; Vascular System; blood pressure elevation; calcification; cardiovascular risk factor; clinically significant; cytokine; design; endoplasmic reticulum stress; endothelial dysfunction; gene therapy; high risk; hypertensive; improved; male; mortality; mouse model; multidisciplinary; novel therapeutics; overexpression; prevent; surgical menopause; 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 - 高血压诱导的血管病理学的中心机制，公众 健康危机，仍然未知。高血压患者的不良事件率仍然很大 规定了这些治疗性的，高血压患者仍然对这些疗法有抵抗力。那， 关键的未满足需求是确定基于机制的可挽救血管功能和 既定高血压的结构。试点数据表明，将健康的Treg转移到小鼠中 由血管紧张素II（ANG II）诱导的高血压诱导的高血压改善了血管内皮 功能和结构。我们显示出在 可能导致NOX2和内质网（ER）应激的Treg凋亡 依赖机制。 Treg细胞中Stim1的过表达引起Treg细胞凋亡。这 高血压小鼠中树突状细胞的消耗改善了动脉功能，动脉纤维化降低和 通过减少INFγ和IL-1β从树突状细胞释放的钙化和ER的抑制 内皮细胞中的压力。中心假设是treg细胞中的stim1过表达， ROS和ER应力机制，导致Treg细胞凋亡并减少IL-10释放，从而增加 树突状细胞活性导致促炎细胞因子释放（INFγ和IL-1β）和A 减少抗炎IL-10释放，导致内皮细胞中的ER应力诱导和 血管病理学。为了推进翻译科学，我们将在两凯尼一号中检验假设 夹子（2K1C）高血压小鼠ANG II依赖性。特定目的＃1：确定已建立 高血压，stim1表达在引起Treg细胞凋亡的Treg细胞中增加，IL-10降低 释放和血管病理学。破坏treg细胞中的stim1表达将恢复treg细胞 数量，IL-10水平，并改善血管内皮功能并减少纤维化和钙化 建立的高血压。特定目的＃2：描述IL-10发行的减少，因为 Treg中的凋亡，增加了树突状细胞活性以释放IFNγ和IL-1β和Blunt IL-10释放，这 通过诱导内皮细胞中的ER应力机理引起血管病理，因此 耗尽树突状细胞或操纵内皮细胞中的ER应力改善血管内皮 功能并减少由2K1C诱导的已建立高血压的纤维化和计算。这些研究 是NHLBI任务的核心，并解决了NHLBI中概述的所有目标和多种策略 战略计划。这些研究将解决1）需要进一步阐明生物学机制和 免疫细胞贡献的病理过程，2）免疫之间的相互作用 系统和血管系统作为优先研究主题，3）促进翻译科学， 我们将在2K1C小鼠模型中检验假设。