PPAR gamma and Nox4 in pulmonary hypertension

描述(由申请人提供)：尽管有现有的治疗方法，但肺动脉高压(PH)会导致显著的发病率和死亡率。PPARg作为PH治疗的新靶点，是本研究的重点。越来越多的证据表明，慢性缺氧和其他导致PH的原因与NADPH氧化酶NOX4的表达和活性增加有关。NOX4产生的活性氧参与了血管收缩、肺血管细胞增殖和肺高压的发病。在小鼠模型中，用噻唑烷二酮配体刺激PPARg可减少NOX4的表达和活性，并减轻缺氧诱导的血管重构、右室肥厚和肺动脉高压。初步数据证实，在特发性肺动脉高压患者的内皮细胞中，NOX4表达上调。因此，这一建议验证了PPARg激活提供了一种新的策略来减轻缺氧诱导的NOX4表达、氧化应激、血管重构和PH的假说。为了探索这一假说，目标1将使用内皮和平滑肌靶向的NOX4基因敲除小鼠来研究NOX4在低氧诱导的PH中的作用以及PPARg对其调节。AIM 2将使用内皮和平滑肌靶向的PPARg基因敲除或过度表达的小鼠来定义肺血管细胞间隔，这些细胞间隔对于PPARg配体诱导的NOX4和PH的变化至关重要。目的3将研究PPARg激活减弱肺血管中NOX4表达的分子机制。体外研究将使用暴露在低氧环境中的人肺动脉平滑肌或内皮细胞进行。这项建议的长期目标是确定PPARg激活减轻PH的机制，并促进新的PH治疗的发展。 与公共卫生相关：肺部高血压，也称为肺动脉高压，是一种破坏性的疾病，影响到许多患者，目前还没有有效的治疗方法。这项建议利用动物模型探索了一种新型的肺动脉高压治疗方法，不仅检查了这种新治疗策略的有效性，还检查了它的基本作用机制。这些研究有可能确定可应用于肺动脉高压患者的新治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: High blood pressure in the lung, also called pulmonary hypertension, is a devastating condition that affects many patients and for which there are no effective therapies. This proposal explores a new type of therapy for pulmonary hypertension using an animal model by examining not only the efficacy of this new treatment strategy but also the basic mechanisms by which it works. These studies have the potential to identify novel treatment strategies that could be applied to patients with pulmonary hypertension.