Reactive Oxygen Species in Vascular Disease

血管疾病中的活性氧

• 批准号: 9124895
• 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
• 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/9124895
• 关键词: Accounting; Address; Animals; Attenuated; Binding; Biology; Blood Vessels; Bone Morphogenetic Proteins; Cause of Death; Cell Proliferation; Cessation of life; Clinical; Cyclic AMP; Data; Development; Diagnosis; Disease; Elements; Endothelial Cells; Failure; Foundations; Genetic Techniques; Grant; Health; Heart Hypertrophy; Heart failure; Human; Hypoxia; Imaging Device; In Situ; Lesion; Lung; Mediating; Mediator of activation protein; Modeling; Molecular Genetics; Mus; NADPH Oxidase; Oxidants; Pathologic; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Play; Production; Protein Isoforms; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; Rattus; Reactive Oxygen Species; Research; Resistance; Rodent Model; Role; SHH gene; Signal Transduction; Specimen; Testing; Therapeutic; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular Proliferation; Vascular remodeling; Vascular resistance; Ventricular; angiogenesis; base; cyanine dye 5; hemodynamics; human disease; in vivo; in vivo imaging; inhibitor/antagonist; innovation; loss of function; mouse model; novel; novel therapeutics; pressure; prevent; pulmonary arterial hypertension; pulmonary artery endothelial cell; response

 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。对病理机制的了解不足对针对该疾病的临床方法造成了障碍，该疾病通常与快速且侵袭性的血管重塑、丛状病变 (PL) 形成和右心室衰竭有关。 NADPH 氧化酶 (Noxs) 产生的活性氧 (ROS) 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，但在 PAH 中尚无 Nox1 的信息。重要的是，Nox1 在血管壁增厚和 PL 形成中的功能作用尚不清楚。我们提出 Nox1 在通过骨形态发生蛋白拮抗剂 Gremlin1 促进增殖和血管重塑方面发挥新作用。这一假设基于最近 Gremlin1 与 PAH 的关联，以及我们支持 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EC Gremlin1的上游和下游介体（包括声波刺猬和CREB）中所起的作用是完全未知的。我们之前的目标是开发一种高选择性且有效的 Nox1 抑制剂。这种抑制剂以及其他分子遗传学技术可以识别缺氧诱导的 PAH 中涉及 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。这将通过解决以下目标进行测试：（1）探讨Nox1的表达及其对缺氧条件下人肺内皮细胞增殖中ROS产生和Gremlin1介导的信号传导的贡献； (2) 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 小鼠模型的血流动力学； (3) 确定 Nox1 抑制剂雾化是否可以预防和/或逆转血管闭塞性 PAH 大鼠模型中的 RV 衰竭。这一范式转变的提议揭示了 Gremlin1-Nox1 在 PAH 和 RV 衰竭中的新作用。该研究计划以令人信服的初步数据为基础，预计将开辟血管生物学的新研究领域，并且在概念和技术上都具有创新性。从治疗的角度来看，通过雾化输送一种新型且高度特异性的 Nox1 抑制剂来破坏肺血管内皮中的这条通路，预计将成为新药物疗法的坚实基础。