Hypoxic factors in pulmonary hypertension

肺动脉高压的缺氧因素

• 批准号: 9173032
• 负责人: Aftab Ahmad
• 金额: $ 35.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173032
• 关键词: ADORA2A gene; Adenosine; Altitude; Binding; Blood Vessels; Cell Proliferation; Cells; Chronic; DNA; Disease; Elements; Endothelial Cells; Endothelium; Fibroblasts; Genes; Genetic Polymorphism; Genetic Transcription; Glycolysis; Goals; Growth; Heart failure; Heritability; Human; Hypoxemia; Hypoxia; Individual; Investigation; Knock-out; Lead; Lung; Lung diseases; Medial; Mediating; Mediator of activation protein; Metabolic Pathway; Modeling; Molecular; Morbidity - disease rate; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Pattern; Pentosephosphate Pathway; Pharmacology; Phenotype; Play; Polycythemia; Prevention; Process; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Receptor Inhibition; Reporting; Research; Role; SU 5416; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Testing; Therapeutic Intervention; Tissues; Vascular Endothelial Growth Factors; Vascular remodeling; autocrine; blocking factor; constriction; gain of function mutation; human disease; in vivo; insight; knock-down; loss of function mutation; mortality; new therapeutic target; novel; paracrine; pressure; public health relevance; pulmonary arterial hypertension; receptor; small hairpin RNA; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Severe pulmonary hypertension is a progressive and irreversible disease that often leads to mortality due to right heart failure. The pathogenesis of pulmonary hypertension involves proliferation of cells, including endothelial cells (intimal remodeling), in the vessel walls of pulmonary arteries resulting in remodeling and pulmonary hypertension. Several factors implicated in the remodeling process are driven by hypoxia. One mechanism by which cells respond to hypoxia is by stabilization of hypoxia-inducible transcription factors (HIFs), HIF-1alpha and HIF-2alpha. Independent studies suggest that both HIF-1alpha and HIF-2alpha are important mediators in PH. However, recent investigations have reported a marked increase in HIF-2alpha gene locus polymorphism in individuals adapting to high altitudes, suggesting a role of HIF-2alpha in PH. Mechanism by which HIF-2alpha influences pulmonary vascular remodeling and PH, independent of HIF-1alpha is not known. This proposal is focused on understanding the role of HIF-2alpha and its pathways in the pathogenesis of pulmonary hypertension. We have recently identified a new pathway, the HIF-2alpha-A2A receptor pathway, by which HIF-2alpha can promote endothelial proliferation, independent of HIF-1alpha. We hypothesize that hypoxia increases endothelial proliferation and vascular remodeling through a HIF-2alpha and A2A receptor-dependent mechanism and that this is an important step in the pathogenesis of PH. Additionally, we have also identified HIF-1alpha in smooth muscle cell proliferation, independent of HIF-2alpha. The proposed studies are divided into three aims. Aim 1 will elucidate mechanisms by which hypoxia and HIFs influence endothelial growth using cultured primary pulmonary endothelial cells as well as endothelial cells derived from hypertensive rats. The second aim will be used to test the hypothesis that inhibition or knockdown of HIFs, particularly HIF-2alpha will limit vascular remodeling and PA pressures in a rat model of PAH. The third aim will test whether inhibition or knockdown of A2A receptor, a downstream transcriptional target of HIF-2alpha, can mitigate remodeling and PA pressures in a rat model of PAH. The in vivo aims will investigate effects using both a prevention model and a rescue model. Results of the proposed research will help provide insights into hypoxic pathways that influence pulmonary vascular remodeling and offer alternative targets for treatment of PH.

描述（由申请人提供）：重度肺动脉高压是一种进行性和不可逆的疾病，通常因右心衰竭导致死亡。肺动脉高压的发病机制涉及肺动脉的血管壁中的细胞增殖，包括内皮细胞（内膜重塑），导致重塑和肺动脉高压。在重塑过程中涉及的几个因素是由缺氧驱动的。细胞对缺氧反应的一种机制是通过稳定缺氧诱导转录因子（HIF），HIF-1 α和HIF-2 α。独立的研究表明，HIF-1 α和HIF-2 α都是重要的介质在PH。然而，最近的调查报告了一个显着增加HIF-2 α基因位点多态性的个人适应高海拔地区，表明HIF-2 α在PH的作用。HIF-2 α影响肺血管重构和PH的机制，独立于HIF-1 α是未知的。本研究的重点是了解HIF-2 α及其通路在肺动脉高压发病机制中的作用。 我们最近发现了一个新的途径，HIF-2 α-A2 A受体途径，通过该途径HIF-2 α可以促进内皮细胞增殖，而不依赖于HIF-1 α。我们假设缺氧通过HIF-2 α和A2 A受体依赖性机制增加内皮细胞增殖和血管重塑，这是PH发病机制中的重要步骤。此外，我们还确定了HIF-1 α在平滑肌细胞增殖中的作用，独立于HIF-2 α。拟议的研究分为三个目标。目的1：利用原代培养的肺内皮细胞和高血压大鼠内皮细胞，阐明缺氧和HIF影响内皮细胞生长的机制。第二个目的将用于检验抑制或敲低HIF，特别是HIF-2 α将限制PAH大鼠模型中的血管重塑和PA压力的假设。第三个目标将测试是否抑制或敲低A2 A受体（HIF-2 α的下游转录靶点）可以减轻PAH大鼠模型中的重塑和PA压力。 体内目标将研究使用预防模型和挽救模型的效果。拟议的研究结果将有助于深入了解影响肺血管重塑的缺氧途径，并为PH的治疗提供替代靶点。