PPAR gamma and Nox4 in pulmonary hypertension

描述（由申请人提供）：尽管现有的治疗方法，肺动脉高压（PH）引起显著的发病率和死亡率。本研究将过氧化物酶体增殖物激活受体（ppar）作为PH治疗的新靶点。不断发展的证据表明，慢性缺氧和其他原因的PH与NADPH氧化酶Nox4的表达和活性增加有关。Nox4产生活性氧，参与血管收缩、肺血管细胞增殖和PH发病。在小鼠模型中，用噻唑烷二酮配体刺激PPARg可降低Nox4的表达和活性，并减轻缺氧诱导的血管重构、右心室肥厚和肺动脉高压。初步数据证实，Nox4在特发性肺动脉高压患者的内皮细胞中表达上调。因此，本研究验证了PPARg的激活为降低缺氧诱导的Nox4表达、氧化应激、血管重塑和PH提供了一种新的策略。为了验证这一假设，Aim 1将使用内皮和平滑肌靶向Nox4敲除小鼠，研究Nox4在缺氧诱导的PH中的作用以及PPARg对其的调节。目的2将使用内皮和平滑肌靶向PPARg敲除或过表达小鼠来确定肺血管细胞室，这些细胞室对于PPARg配体诱导的Nox4和ph的改变至关重要。目的3将研究PPARg激活减弱肺血管中Nox4表达的分子机制。体外研究将使用缺氧暴露的人肺动脉平滑肌或内皮细胞进行。本提案的长期目标是确定PPARg活化降低PH的机制，并促进新的PH治疗的发展。

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.