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PPAR gamma and Nox4 in pulmonary hypertension

PPAR gamma and Nox4 in pulmonary hypertension
PPAR γ 和 Nox4 在肺动脉高压中的作用
批准号:
8207904
负责人:
C MICHAEL HART
金额:
$32.44万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-01-01 至 2014-12-31

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中文摘要
翻译
尽管现有的治疗方法,肺动脉高压(PH)导致显着的发病率和死亡率。 该提案将过氧化物酶体增殖物激活受体γ(PPARg)作为新的靶点 PH治疗。不断发展的证据表明,慢性缺氧和PH的其他原因是 与NADPH氧化酶Nox4的表达和活性增加相关。Nox4生成 有助于血管收缩、肺血管细胞增殖和 PH发病机制。用噻唑烷二酮配体刺激PPARg降低了PPARg的表达, Nox 4的活性,并减弱缺氧诱导的血管重塑,右心室肥大, 和肺动脉高血压。初步数据证实,Nox4在人乳腺癌中上调, 来自特发性肺动脉高压患者的内皮细胞。因此本 一项提案检验了PPARg的激活提供了一种新的策略来减弱 缺氧诱导的Nox4表达、氧化应激、血管重构和PH。 假设,目的1将研究Nox 4在缺氧诱导的PH中的作用及其通过PPARg的调节 使用内皮和平滑肌靶向的Nox4敲除小鼠。Aim 2将使用内皮细胞, 平滑肌靶向PPARg敲除或过表达小鼠以确定肺血管细胞 这些区室对于PPARg配体诱导的Nox 4和PH改变至关重要。 研究PPARg激活减弱Nox 4表达的分子机制。 肺血管体外研究将使用暴露于缺氧的人肺 动脉平滑肌或内皮细胞。该提案的长期目标是确定 PPARg激活减弱PH并促进新PH发展的机制 疗法
英文摘要
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.
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Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
  • 批准号:
    8440548
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2012
  • 负责人:
    C MICHAEL HART
  • 依托单位:
海外基金