PPAR gamma and Nox4 in pulmonary hypertension

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是PPARg的新靶点 在PH治疗中。越来越多的证据表明，慢性缺氧和其他导致PH的原因是 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、肺血管细胞增殖的活性氧物种，以及 PH发病机制。用噻唑烷二酮配体刺激PPARg可降低其表达和 NOX4的活性和减轻低氧诱导的血管重构，右室肥厚， 和小鼠模型中的肺动脉高压。初步数据证实，NOX4在 特发性肺动脉高压患者的内皮细胞。因此，这 Proposal检验了PPARg激活提供了一种新的减毒策略的假设 低氧诱导的NOX4表达、氧化应激、血管重构和PH。要探索这一点 假设，目标1将研究NOX4在低氧诱导的PH中的作用以及PPARg对其的调节 使用内皮和平滑肌靶向的NOX4基因敲除小鼠。目标2将使用内皮细胞-和 以平滑肌为靶点的PPARg基因敲除或过表达小鼠确定肺血管细胞 对PPARg配体诱导的NOX4和PH改变至关重要的隔室。目标3将 检测PPARg激活抑制NOX4表达的分子机制 肺血管系统。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。这项提案的长期目标是界定 PPARg激活减弱PH并促进新PH发生的机制 心理治疗。

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.