Reactive Oxygen Species in Vascular Disease

血管疾病中的活性氧

基本信息

批准号：
8985000
负责人：
Patrick J Pagano
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8985000
关键词：
Address Amines Animals Arteries Attenuated Binding Biology Blood Vessels Bone Morphogenetic Proteins CREB1 gene Cardiac Cause of Death Cell Proliferation Cells Cessation of life Clinical Cyclic AMP Data Development Diagnosis Disease Elements Endothelial Cells Erinaceidae Failure Foundations Genetic Techniques Grant Heart failure Human Hypoxia In Situ Ions Lead Lesion Lung Mediating Mediator of activation protein Modeling Molecular Genetics Mus NADP NADPH Oxidase Oxidants Pathologic Pathway interactions Patients Pharmacotherapy Play Production Protein Isoforms Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Rattus Reactive Oxygen Species Research Resistance Rodent Model Role SHH gene Signal Transduction Son Stream Testing Therapeutic Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular remodeling Ventricular Work base cyanine dye 5 hemodynamics human disease in vivo in vivo imaging inhibitor/antagonist innovation man mouse model novel prevent public health relevance pulmonary arterial hypertension pulmonary artery endothelial cell tool

项目摘要

DESCRIPTION (provided by applicant): Right ventricular (RV) failure is the leading cause of death in patients with pulmonary arterial hypertension (PAH). Hypoxia-induced PAH is a common form of the disease leading to heart failure. A poor understanding of pathologic mechanisms presents a barrier to clinical approaches targeting the disease, which is often associated with rapid and aggressive vascular remodeling, plexiform lesion (PL) formation, and RV failure. Reactive oxygen species (ROS) from NADPH oxidases (Noxs) are implicated in PAH and previous data support a role for Nox2 in pulmonary vascular endothelial (EC) proliferation. However, despite its expression in the pulmonary vascular wall, no information exists for Nox1 in PAH. Importantly, a functional role for Nox1 in vascular wall thickening and PL formation is entirely unknown. We propose a novel role for Nox1 in promoting proliferation and vascular remodeling via Gremlin1, an antagonist of bone morphogenetic protein. This hypothesis is based on a recent association of Gremlin1 with PAH and our preliminary data supporting Nox1-mediated Gremlin1 expression in human pulmonary artery endothelial cell (HPAEC) proliferation. In fact, the role that any Nox plays in mediating upstream and downstream mediators of EC Gremlin1, including sonic hedgehog and CREB, is entirely unknown. Our previous aims led to development of a highly-selective and efficacious Nox1 inhibitor. This inhibitor, as well as other molecular genetic techniques, allows identification of multiple new pathways involving Gremlin1 in hypoxia-induced PAH. We will test the central hypothesis that Nox1 propagates Gremlin1-mediated signaling, thereby promoting hypoxia- induced PAH and RV failure. This will be tested by addressing the following aims: (1) To interrogate the expression of Nox1 and its contribution to ROS production and Gremlin1- mediated signaling in human pulmonary endothelial cell proliferation under hypoxic conditions; (2) To determine whether specific Nox1 inhibitor permeates and targets hypoxia-induced endothelial ROS signaling and Gremlin1 expression and attenuates hemodynamics in a mouse model of PAH; and (3) To determine whether aerosolization of Nox1 inhibitor prevents and/or reverses RV failure in a rat model of vascular occlusive PAH. This paradigm-shifting proposal uncovers a novel role for Gremlin1-Nox1 in PAH and RV failure. The research plan, built on compelling preliminary data, is expected to open up a new field of inquiry in vascular biology and is conceptually and technologically innovative. From a therapeutic standpoint, delivery of a novel and highly-specific Nox1 inhibitor to disrupt this pathway in the pulmonary vascular endothelium via aerosolization is expected to serve as a firm foundation for new drug therapies.

描述（由申请人提供）：右心室（RV）衰竭是肺动脉高压（PAH）患者死亡的主要原因。缺氧引起的 PAH 是导致心力衰竭的常见疾病。对病理学了解甚少。机制对针对该疾病的临床方法提出了障碍，该疾病通常与快速且侵袭性的血管重塑、丛状病变 (PL) 形成和 NADPH 产生的活性氧 (ROS) 衰竭有关。氧化酶 (Nox) 与 PAH 有关，之前的数据支持 Nox2 在肺血管内皮 (EC) 增殖中的作用。然而，尽管 Nox1 在肺血管壁中表达，但尚无关于 Nox1 在 PAH 中的功能作用的信息。 Nox1 在血管壁增厚和 PL 形成中的作用尚不清楚，Nox1 通过 Gremlin1（一种骨形态发生拮抗剂）促进增殖和血管重塑。这一假设基于 Gremlin1 与 PAH 的最新关联，以及支持 Nox1 介导的 Gremlin1 在人肺动脉内皮细胞 (HPAEC) 增殖中表达的初步数据。事实上，任何 Nox 在介导上游和下游介质中都发挥着作用。 EC Gremlin1（包括 sonic humighog 和 CREB）的作用完全未知。我们之前的目标是开发一种高度选择性且有效的 Nox1 抑制剂。与其他分子遗传学技术一样，可以识别缺氧诱导的 PAH 中 Gremlin1 的多种新途径，我们将测试 Nox1 传播 Gremlin1 介导的信号传导，从而促进缺氧诱导的 PAH 和 RV 衰竭的中心假设。以下目标： (1) 探讨缺氧条件下 Nox1 的表达及其对人肺内皮细胞增殖中 ROS 产生和 Gremlin1 介导的信号传导的贡献；确定特定的 Nox1 抑制剂是否渗透并靶向缺氧诱导的内皮 ROS 信号传导和 Gremlin1 表达，并减弱 PAH 小鼠模型中的血流动力学；以及 (3) 确定 Nox1 抑制剂的雾化是否可以预防和/或逆转 PAH 大鼠模型中的 RV 衰竭这项范式转变的提议揭示了 Gremlin1-Nox1 在 PAH 和 RV 衰竭中的新作用。结论性的初步数据预计将开辟血管生物学的新研究领域，并且从治疗的角度来看，提供一种新型且高度特异性的 Nox1 抑制剂可通过雾化破坏肺血管内皮中的这一途径。预计将成为新药疗法的坚实基础。