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-高血压引起的血管病理的中心机制，公众 健康危机，仍然未知。高血压患者的不良事件发生率仍然很高。 开出了这些治疗性的药物，三分之二的高血压患者仍然对这些疗法产生抵触。因此， 关键的未得到满足的需要是确定基于机制的可治疗靶点，以挽救血管功能和 结构在已建立的高血压。试验数据显示，将健康的Treg转移到小鼠身上 血管紧张素II(Ang II)输注改善血管内皮细胞 功能和结构。我们发现间质相互作用分子1(STIM1)表达增加。 可能通过NOX2和内质网应激导致Treg凋亡的Treg- 依赖机制。STIM1在Treg细胞中的过表达可导致Treg细胞的凋亡。这个 去除高血压小鼠的树突状细胞可改善动脉功能，减少动脉纤维化和 树突状细胞分泌的干扰素γ和IL-1β减少引起的钙化及其对ER的抑制 血管内皮细胞的压力。中心假设是STIM1在Treg细胞中过表达，通过 ROS和ER应激机制，导致Treg细胞凋亡和IL-10释放减少，从而增加 树突状细胞活性导致促炎细胞因子(干扰素γ和IL-1β)释放增加 抗炎IL-10释放减少导致内皮细胞内质网应激诱导 血管病理学。为了推进翻译科学，我们将在两肾一号中检验这一假说。 CLIP(2K1C)高血压小鼠Ang II依赖。具体目标#1：确定已建立的 高血压，STIM1在Treg细胞中表达增加，导致Treg细胞凋亡，IL-10下降 释放，和血管病理。因此，破坏Treg细胞中STIM1的表达将恢复Treg细胞 IL-10水平，改善血管内皮功能，减少纤维化和钙化 确诊为高血压。具体目标2：描绘IL-10释放的减少，因为 Treg中的细胞凋亡，增加树突状细胞释放干扰素γ和IL-1β的活性，并钝化IL-10的释放，从而 通过诱导内皮细胞的内质网应激机制导致血管病理，因此 清除树突状细胞或调控内皮细胞内质网应激改善血管内皮细胞 在2K1C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NHLBI使命的核心，并处理NHLBI中概述的所有目标和多个战略 战略规划。这些研究将解决1)进一步阐明生物机制和 病理过程中免疫细胞的贡献，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，以及3)促进翻译科学， 我们将在2K1C小鼠模型中验证这一假设。