Formyl peptide receptor activation induces vascular plasticity and remodeling in hypertension

项目概要：温塞斯劳、卡米拉·F。 高血压的主要病理生理特征之一是血管的存在。 改建。因此，已有研究表明，100%的高血压受试者会出现小动脉重构。 然而，在了解导致血管重塑的确切触发因素方面，文献中存在空白。 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，免疫机制在高血压的病理生理学中起作用。甲酰肽 受体(Fpr)-1是一种模式识别受体，在先天免疫功能中起着至关重要的作用。 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通路之一 运动由fpr-1介导。最近，我们观察到该受体在动脉中表达。因此， 我们质疑为什么在白细胞中对免疫防御和细胞运动至关重要的受体会 在动脉中表达并发挥功能？我们观察到，动脉中fpr-1的激活对血管紧张素转换酶激活具有重要意义。 肌动蛋白的时间重组，从而迅速诱导肌动蛋白聚合。 FPR-1是一种G蛋白偶联受体，可与细菌产生的N-甲酰基多肽结合 退化。有趣的是，线粒体带有其细菌祖先的特征。因此，两者 线粒体和细菌来源的多肽在其N端有一个甲酰基。因此，N-甲酰基 多肽(NFP)，无论来源如何，都被fpr-1识别为病原体，并因此在启动过程中发挥作用。 发炎的症状。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，我们有理由认为，肠道渗漏细菌的协同作用 NFP和细胞损伤衍生的线粒体NFP导致FPR-1激活。因此，fpr-1的激活 可能是通过肌动蛋白聚合诱导血管重塑的触发因素，并随后引发高血压。 这项计划中的研究特别适合NHLBI早期调查员(ESI)-研究项目 格兰特(R01)。它是创新的，拥有一支强大的翻译和多学科研究团队的合作者 他们有能力和专业知识使这个项目取得成功。作为一家独立的ESI，我的短期 目标是使用最先进的方法，包括文化压力肌图仪、基因工程技术、 以及来自人类和动物的动脉来探索血管免疫网络背后的主要驱动力 高血压中的功能障碍。

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.