PPAR gamma and Nox4 in pulmonary hypertension

PPAR γ 和 Nox4 在肺动脉高压中的作用

• 批准号: 8598927
• 负责人: C MICHAEL HART
• 金额: $ 31.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598927
• 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; Peroxisome Proliferator-Activated Receptors; 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

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.

尽管现有疗法，肺动脉高压（PH）仍会引起明显的发病率和死亡率。 该建议重点是过氧化物酶体增殖物激活的受体伽马（PPARG）作为新目标 在pH疗法中。不断发展的证据表明，慢性缺氧和其他pH值为 与NADPH氧化酶NOX4的表达和活性增加有关。 NOX4生成 有助于血管收缩，肺血管细胞增殖和 pH发病机理。用噻唑烷二酮配体刺激PPARG降低了表达和 NOX4的活性并减弱缺氧引起的血管重塑，右心肥大， 小鼠模型中的肺动脉高压。初步数据确认NOX4已上调 特发性肺动脉高压患者的内皮细胞。因此，这个 提案研究了PPARG激活提供了一种新颖策略的假设 缺氧诱导的NOX4表达，氧化应激，血管重塑和pH值。探索这个 假设，AIM 1将检查NOX4在缺氧诱导的pH中的作用及其对PPARG的调节 使用靶向肌肉和平滑肌的NOX4敲除小鼠。 AIM 2将使用内皮 - 和 平滑肌肉针对的PPARG敲除或过表达小鼠以定义肺血管细胞 对于Nox4和pH中PPARG配体诱导的改变至关重要的隔室。目标3意志 检查PPARG激活减弱NOX4表达的分子机制 肺脉管系统。体外研究将使用缺氧暴露的人肺进行 动脉平滑肌或内皮细胞。该提议的长期目标是定义 PPARG激活减弱pH并促进新pH的发展的机制 治疗。