Pulmonary Vasoreactivity Following Chronic Hypoxia

慢性缺氧后的肺血管反应性

基本信息

批准号：
7522559
负责人：
THOMAS C RESTA
金额：
$ 37.5万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7522559
关键词：
Address Adult Agonist Agreement Altitude Animals Blood Blood Vessels Calcium Caliber Cations Cause of Death Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Clinical Conscious Constriction procedure Data Development Disease Edema Environment Epithelial Cells Figs - dietary Generations Heart Heart failure Human Hypertension Hypoxia Kidney Laboratories Link Lung Lung diseases Measures Mediating Membrane Methods Microfilaments Modeling Molecular Morbidity - disease rate Muscle Contraction Muscle Hypertonia Muscle Tonus Myosin Light Chain Kinase Myosin Light Chains NADPH Oxidase Obstructive Lung Diseases Outcome Pathogenesis Pathway interactions Peripheral Personal Satisfaction Phosphorylation Phosphotransferases Pilot Projects Play Polycythemia Public Health Pulmonary Circulation Pulmonary Emphysema Pulmonary Heart Disease Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Rattus Reactive Oxygen Species Relaxation Research Resistance Rho-associated kinase Right-On Role Sarcolemma Second Messenger Systems Signal Transduction Sleep Apnea Syndromes Testing Tubular formation Up-Regulation Vascular Smooth Muscle Vasoconstrictor Agents Work arterial remodeling base concept experience fetal interest kinase inhibitor man mortality myosin phosphatase novel pressure research study response vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Chronic hypoxia (CH) associated with obstructive lung diseases and sleep apnea leads to pulmonary hypertension. Elevated basal vascular smooth muscle (VSM) tone and enhanced vasoconstrictor reactivity play a prominent role in mediating CH-induced pulmonary hypertension. However, the mechanisms by which CH elicits these vasoconstrictor responses are not understood. Pilot studies have revealed a novel effect of CH to promote myogenic tone and enhance vasoconstrictor reactivity through a RhoA/Rho kinase-dependent Ca2+-sensitization pathway in pulmonary VSM. These studies further suggest that CH-induced VSM membrane depolarization stimulates RhoA/Rho kinase independent of changes in VSM free Ca2+ levels, and provide intriguing evidence for a major contribution of NADPH oxidase (NOX)-derived reactive oxygen species (ROS) to this response. Therefore, the proposed studies will investigate the central hypothesis that CH- induced VSM membrane depolarization mediates NOX-dependent stimulation the RhoA/Rho kinase pathway leading to increased myogenic and agonist-induced myofilament Ca2+ sensitivity. This hypothesis will be addressed by the following specific aims: Specific Aim #1: Identify the intracellular signaling mechanism responsible for elevated myogenic and agonist-dependent constriction following CH. We hypothesize that CH augments pulmonary arterial myogenic tone and agonist-mediated constriction via RhoA/ROK-induced VSM Ca2+ sensitization. Specific Aim #2: Determine the contribution of membrane depolarization to increased basal and agonist-induced pulmonary arterial constriction following CH. Based on pilot data outlined below, the working hypothesis for this aim is that CH-induced VSM membrane depolarization stimulates the RhoA/Rho kinase pathway leading to increased basal and agonist-induced myofilament Ca2+ sensitivity. Specific Aim #3: Establish the role of NOX-derived ROS in mediating enhanced myogenic and agonist-dependent pulmonary vasoconstrictor reactivity following CH. We hypothesize that depolarization-induced ROS-generation by NOX upregulates basal and agonist-induced RhoA/Rho kinase signaling in pulmonary VSM following CH. The proposed research will employ whole animal, isolated lung, isolated vessel and molecular approaches to establish a novel mechanistic link between VSM membrane depolarization, NOX-derived ROS generation, and RhoA/ROK signaling in the hypertensive pulmonary circulation. Collectively, these outcomes are expected to fundamentally advance our understanding of signaling mechanisms by which ROK regulates vascular tone, as well as vasoconstrictor mechanisms that contribute to the development of pulmonary hypertension. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary diseases (COPD) such as emphysema and chronic bronchitis are established major causes of mortality and morbidity in the U.S. COPD is currently the fourth leading cause of death in the U.S. and is predicted to be the third leading cause of death by 2020 (Sin, D.D. and Man, S.F. Proc Am Thorac Soc 2:8-11, 2005). The aim of this study is to determine the factors responsible for the development of pulmonary hypertension in a rat model of COPD. Such disease states cause poor oxygenation of the blood (hypoxia), and the resultant pulmonary hypertension leads to right heart failure and mortality in humans.

描述（由申请人提供）：与阻塞性肺病和睡眠呼吸暂停相关的慢性缺氧（CH）会导致肺动脉高压。基础血管平滑肌 (VSM) 张力升高和血管收缩反应性增强在介导 CH 诱发的肺动脉高压中发挥着重要作用。然而，CH 引发这些血管收缩反应的机制尚不清楚。初步研究揭示了 CH 通过肺 VSM 中 RhoA/Rho 激酶依赖性 Ca2+ 敏化途径促进肌源张力和增强血管收缩反应性的新作用。这些研究进一步表明，CH 诱导的 VSM 膜去极化刺激 RhoA/Rho 激酶，与 VSM 游离 Ca2+ 水平的变化无关，并为 NADPH 氧化酶 (NOX) 衍生的活性氧 (ROS) 对此反应的主要贡献提供了有趣的证据。因此，拟议的研究将调查以下中心假设：CH 诱导的 VSM 膜去极化介导 NOX 依赖性刺激 RhoA/Rho 激酶途径，导致肌源性和激动剂诱导的肌丝 Ca2+ 敏感性增加。这一假设将通过以下具体目标来解决：具体目标#1：确定导致 CH 后肌源性和激动剂依赖性收缩升高的细胞内信号传导机制。我们假设 CH 通过 RhoA/ROK 诱导的 VSM Ca2+ 敏化增强肺动脉肌源性张力和激动剂介导的收缩。具体目标#2：确定膜去极化对 CH 后基础和激动剂诱导的肺动脉收缩增加的影响。基于下面概述的试验数据，该目标的工作假设是 CH 诱导的 VSM 膜去极化刺激 RhoA/Rho 激酶途径，导致基础和激动剂诱导的肌丝 Ca2+ 敏感性增加。具体目标#3：确定 NOX 衍生的 ROS 在介导 CH 后增强的肌源性和激动剂依赖性肺血管收缩反应性中的作用。我们假设 NOX 去极化诱导的 ROS 生成上调 CH 后肺 VSM 中基础和激动剂诱导的 RhoA/Rho 激酶信号传导。拟议的研究将采用整体动物、离体肺、离体血管和分子方法来建立高血压肺循环中 VSM 膜去极化、NOX 衍生的 ROS 生成和 RhoA/ROK 信号传导之间的新型机制联系。总的来说，这些结果预计将从根本上增进我们对 ROK 调节血管张力的信号机制以及导致肺动脉高压发生的血管收缩机制的理解。公共卫生相关性：肺气肿和慢性支气管炎等慢性阻塞性肺疾病 (COPD) 已被确定为美国死亡和发病的主要原因。COPD 目前是美国第四大死因，预计将成为美国第三大死因。到 2020 年死亡（Sin、D.D. 和 Man，S.F. Proc Am Thorac Soc 2:8-11， 2005）。本研究的目的是确定 COPD 大鼠模型中导致肺动脉高压发生的因素。这种疾病状态会导致血液氧合不良（缺氧），由此产生的肺动脉高压会导致人类右心衰竭和死亡。