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）：与阻塞性肺部疾病和睡眠呼吸暂停有关的慢性缺氧（CH）导致肺动脉高压。升高的基底血管平滑肌（VSM）张力和增强的血管收缩反应性在介导CH诱导的肺动脉高压方面起着重要作用。但是，尚不清楚CH引起这些血管收缩反应的机制。试点研究揭示了CH通过RhoA/Rho激酶依赖性CA2+ - 敏化途径在肺VSM中促进肌吻合张力并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无VY的CA2+水平的变化无关，并为NADPH氧化酶（NOX）衍生的活性氧（ROS）的主要贡献提供了有趣的证据。因此，拟议的研究将研究中心假设，即CH诱导的VSM膜去极化介导了NOX依赖性刺激RhoA/Rho激酶途径，从而导致肌原性和激动剂诱导的肌膜Ca2+敏感性增加。该假设将通过以下特定目的来解决：具体目的＃1：确定CH后造成肌原性和激动剂依赖性收缩的细胞内信号传导机制。我们假设CH通过RhoA/Rok诱导的VSM Ca2+敏化来增强肺动脉肌张力和激动剂介导的收缩。具体目标＃2：确定膜去极化对CH后基底和激动剂诱导的肺动脉收缩的贡献。根据下面概述的试验数据，此目的的工作假设是CH诱导的VSM膜去极化刺激了RhoA/Rho激酶途径，导致基底和激动剂诱导的肌膜Ca2+敏感性增加。特定目标＃3：确定nox衍生的ROS在CH后介导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，去极化引起的NOX诱导的ROS生成上调了CH后肺VSM中的基底和激动剂诱导的RhoA/Rho激酶信号传导。拟议的研究将采用全动物，孤立的肺，孤立的血管和分子方法，在高血压肺循环中在VSM膜去极化，NOX衍生的ROS产生和RhoA/ROK信号传导之间建立新的机械联系。总体而言，这些结果有望从根本上促进我们对ROK调节血管张力的信号传导机制的理解，以及有助于肺动脉高压发展的血管收缩机制。公共卫生相关性：慢性阻塞性肺部疾病（COPD），例如肺气肿和慢性支气管炎是美国COPD死亡率和发病率的主要原因，目前是美国的第四个主要死亡原因，预计到2020年将是第三大主要原因（SIN，D.D.和MAN，SIN，D.D.和MAN，PROC AM THORAC SOC 2：8-11：8-11 8-11，2005年）。这项研究的目的是确定导致COPD大鼠模型中肺动脉高压发展的因素。这种疾病状态会导致血液氧合不良（缺氧），导致的肺高血压导致人类的心力衰竭和死亡率。