PPAR gamma and Nox4 in pulmonary hypertension

PPAR γ 和 Nox4 在肺动脉高压中的作用

基本信息

批准号：
8207904
负责人：
C MICHAEL HART
金额：
$ 32.44万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207904
关键词：
2,4-thiazolidinedione Affect Animal Model Animals Attenuated Binding Blood Vessels Cell Proliferation Cell Wall Cells Chronic Data Development Disease Endothelial Cells Experimental Models Goals Human Hypertension Hypoxia In Vitro Knock-out Knockout Mice Ligands Lung Mediating Modeling Molecular Morbidity - disease rate Mus NADPH Oxidase Nuclear Nuclear Hormone Receptors Oxidative Stress PPAR gamma Pathogenesis Pathway interactions Patients Platelet-Derived Growth Factor Production Publishing Pulmonary Hypertension Pulmonary artery structure Reactive Oxygen Species Regulation Right Ventricular Hypertrophy Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Therapeutic Effect Thiazolidinediones Transforming Growth Factor beta Vascular remodeling Wild Type Mouse Work activating transcription factor effective therapy hypoxia inducible factor 1 in vivo in vivo Model knockout animal loss of function member mortality mouse model novel novel strategies overexpression promoter protective effect pulmonary arterial hypertension response therapeutic target treatment strategy vasoconstriction

项目摘要

Despite existing therapies, pulmonary hypertension (PH) causes significant morbidity and mortality. This proposal focuses on peroxisome proliferator-activated receptor gamma (PPARg) as a new target in PH therapy. Evolving evidence demonstrates that chronic hypoxia and other causes of PH are associated with increased expression and activity of the NADPH oxidase, Nox4. Nox4 generates reactive oxygen species that contribute to vasoconstriction, pulmonary vascular cell proliferation, and PH pathogenesis. Stimulating PPARg with thiazolidinedione ligands reduces the expression and activity of Nox4 and attenuates hypoxia-induced vascular remodeling, right ventricular hypertrophy, and pulmonary hypertension in a mouse model. Preliminary data confirm that Nox4 is upregulated in endothelial cells from patients with idiopathic pulmonary arterial hypertension. Therefore, this proposal examines the hypothesis that activation of PPARg provides a novel strategy to attenuate hypoxia-induced Nox4 expression, oxidative stress, vascular remodeling and PH. To explore this hypothesis, Aim 1 will examine the role of Nox4 in hypoxia-induced PH and its regulation by PPARg using endothelial- and smooth muscle-targeted Nox4 knockout mice. Aim 2 will use endothelial- and smooth muscle-targeted PPARg knockout or overexpressing mice to define pulmonary vascular cell compartments that are critical for PPARg ligand-induced alterations in Nox4 and PH. Aim 3 will examine the molecular mechanisms by which PPARg activation attenuates Nox4 expression in the pulmonary vasculature. In vitro studies will be performed using hypoxia-exposed human pulmonary artery smooth muscle or endothelial cells. The long-term goals of this proposal are to define mechanisms by which PPARg activation attenuates PH and to facilitate the development of new PH therapy.

尽管有现有的治疗方法，肺动脉高压（PH）仍会导致显着的发病率和死亡率。该提案重点关注过氧化物酶体增殖物激活受体γ（PPARg）作为新靶点在 PH 治疗中。不断变化的证据表明，慢性缺氧和 PH 的其他原因是与 NADPH 氧化酶 Nox4 的表达和活性增加有关。 Nox4 产生活性氧有助于血管收缩、肺血管细胞增殖， PH发病机制。用噻唑烷二酮配体刺激 PPARg 可降低表达并 Nox4 的活性并减弱缺氧引起的血管重塑、右心室肥大、和小鼠模型中的肺动脉高压。初步数据证实 Nox4 在来自特发性肺动脉高压患者的内皮细胞。因此，这该提案检验了以下假设：PPARg 的激活提供了一种新的减弱策略缺氧诱导的 Nox4 表达、氧化应激、血管重塑和 PH。为了探索这个假设，目标 1 将研究 Nox4 在缺氧诱导的 PH 中的作用及其受 PPARg 的调节使用针对内皮和平滑肌的 Nox4 基因敲除小鼠。目标 2 将使用内皮细胞和平滑肌靶向 PPARg 敲除或过表达小鼠来定义肺血管细胞对于 PPARg 配体诱导的 Nox4 和 PH 改变至关重要。目标3将检查 PPARg 激活减弱 Nox4 表达的分子机制肺血管系统。将使用缺氧暴露的人肺进行体外研究动脉平滑肌或内皮细胞。该提案的长期目标是定义 PPARg 激活减弱 PH 并促进新 PH 发展的机制治疗。