Formyl peptide receptor activation induces vascular plasticity and remodeling in hypertension

甲酰基肽受体激活诱导高血压血管可塑性和重塑

• 批准号: 10112987
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 2.63万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112987
• 关键词: Actins; Advanced Development; Affect; Animal Model; Animals; Aorta; Arteries; Attention; Bacteria; Binding; Biological Markers; Blood Circulation; Blood Pressure; Blood Vessels; Cell Death; Cells; Characteristics; Chronic; Data; Dependence; FPR1 gene; Female; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic Engineering; Germ-Free; Goals; Human; Hypertension; Immune; Immune system; Immunobiology; Inflammation; Infusion procedures; Innate Immune System; Interdisciplinary Study; Intrinsic factor; Knockout Mice; Lead; Leaky Gut; Leukocytes; Link; Lipopolysaccharides; Literature; Maintenance; Mediating; Mesentery; Mitochondria; Modeling; Molecular; Movement; Mus; National Heart, Lung, and Blood Institute; Patients; Pattern recognition receptor; Peptides; Play; Rattus; Receptor Activation; Research; Research Personnel; Research Project Grants; Resistance; Role; Sentinel; Signal Pathway; Source; Technology; Testing; Therapeutic; Time; Tissues; Translational Research; Vascular Diseases; Vascular remodeling; base; blood pressure reduction; cell injury; cell motility; cofilin; driving force; fMet-Leu-Phe receptor; formyl peptide; high salt diet; innate immune function; innovation; juvenile animal; male; mature animal; microbiota; network dysfunction; neutrophil; normotensive; novel; novel therapeutic intervention; pathogen; polymerization; pressure; prevent; receptor; sensor; sex; vascular injury; young adult; zonulin

PROJECT SUMMARY WENCESLAU, CAMILLA F. One of the major pathophysiological characteristics of hypertension is the presence of vascular remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling. However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and this may limit our ability to adequately treat and prevent hypertension. Recent evidence implicates immune mechanisms in the pathophysiology of hypertension. Formyl peptide receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune system. In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries. Therefore, we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be expressed and functional in arteries? We observed that activation of FPR-1 in arteries is important for the temporal reorganization of actin, which rapidly induces actin polymerization. FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry. Consequently, both mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus. Therefore, N-formyl peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive animals and humans. Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation. Consequently, FPR-1 activation maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension. This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project Grant (R01). It is innovative and has a strong, translational and multi-disciplinary research team of collaborators that have the capabilities and expertise to make this project successful. As an independent ESI, my short-term goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies, and arteries from humans and animals to explore a major driving force behind vascular-immune network dysfunction in hypertension.

项目概要 WENCESLAU, CAMILLA F. 高血压的主要病理生理学特征之一是血管的存在 重塑。因此，已经表明100%的高血压受试者存在小动脉重塑。 然而，文献中在理解导致血管重塑的确切触发因素方面存在差距，并且 这可能会限制我们充分治疗和预防高血压的能力。 最近的证据表明免疫机制与高血压的病理生理学有关。甲酰基肽 受体（FPR）-1是一种模式识别受体，在先天免疫功能中发挥着至关重要的作用 系统。事实上，诱导肌动蛋白聚合和中性粒细胞的最强大的信号传导途径之一 运动由 FPR-1 介导。最近，我们观察到这种受体在动脉中表达。所以， 我们质疑为什么对白细胞免疫防御和细胞运动至关重要的受体会是 在动脉中表达并发挥功能？我们观察到动脉中 FPR-1 的激活对于 肌动蛋白的时间重组，迅速诱导肌动蛋白聚合。 FPR-1是一种G蛋白偶联受体，可以结合细菌产生的N-甲酰肽 降解。有趣的是，线粒体带有细菌祖先的特征。因此，两者 线粒体和细菌衍生的肽在其 N 末端有一个甲酰基。因此，N-甲酰基 肽（NFP），无论来源如何，都会被 FPR-1 识别为病原体，从而在启动过程中发挥作用 炎症。在这里，我们首次观察到 NFP 存在于高血压患者的循环中。 动物和人类。因此，有理由认为，漏肠源细菌的协同作用 NFP 和细胞损伤衍生的线粒体 NFP 会导致 FPR-1 激活。因此，FPR-1 激活 可能是通过肌动蛋白聚合诱导血管重塑以及随后的高血压的触发因素。 这项计划中的研究特别适合 NHLBI 早期研究者 (ESI) 研究项目 格兰特（R01）。它具有创新性，拥有强大的、转化性和多学科的合作研究团队 拥有使该项目成功的能力和专业知识。作为一个独立的ESI，我的短期 目标是使用最先进的方法，包括文化压力肌动描记器、基因工程技术、 以及人类和动物的动脉，探索血管免疫网络背后的主要驱动力 高血压的功能障碍。