Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia

慢性宫内缺氧引起新生儿肺动脉高压的机制

• 批准号: 10543507
• 负责人: Arlin B Blood
• 金额: $ 78.16万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543507
• 关键词: Acclimatization; Address; Adult; Altitude; Animal Model; Animals; Antioxidants; Ascorbic Acid; Attenuated; Birth; Blood Vessels; Blood flow; Blood gas; Calcium; Cell Hypoxia; Chronic; Communication; Development; Disease; Electron Microscopy; Epigenetic Process; Exposure to; Fetal Development; Fetal Sheep; Fetus; Flow Cytometry; Functional disorder; Gene Expression; HIF1A gene; Hypoxia; Image; In Situ; In Vitro; Incidence; Iron; Link; Lung; Measures; Mediating; Methodology; Methods; MicroRNAs; Mitochondria; Modality; Molecular; Myography; Neonatal; Newborn Infant; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Persons; Placental Insufficiency; Play; Potassium Channel; Pre-Eclampsia; Predisposing Factor; Pregnancy; Pregnancy Complications; Pregnant sheep; Production; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Reactive Oxygen Species; Relaxation; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Sheep; Stress; Sulfur; Sulofenur; Term Birth; Testing; Therapeutic; Tissues; Translations; Vasodilation; Work; antioxidant therapy; cigarette smoking; design; fetal; fetus hypoxia; genetic manipulation; gestational hypoxia; hypoxia inducible factor 1; in utero; in vivo; knock-down; lamb model; large-conductance calcium-activated potassium channels; mitochondrial dysfunction; mortality; neonatal outcome; neonatal pulmonary hypertension; novel; patch clamp; pharmacologic; postnatal; prevent; pulmonary function; response

PROJECT SUMMARY Chronic intrauterine hypoxia is common amongst not only the 140 million people in the world living at high altitudes but also in many complications of pregnancy such as preeclampsia, cigarette smoking, and placental insufficiency. Adaptation of the fetus to chronic hypoxia results in many adverse developmental outcomes, including pulmonary hypertension of the newborn. The BKCa channel is critical to the relaxation of the pulmonary vasculature of the newborn at birth. Recent results from our well-established fetal lamb model of chronic hypoxia during pregnancy points to BKCa channel dysfunction as a causal factor in pulmonary hypertension. The work in this proposal will investigate the mechanistic link between cellular hypoxia and BKCa channel dysfunction. Recent work by others indicates that the ‘master hypoxamir’ miR210, a micro-RNA that is upregulated by HIF-1?, orchestrates pulmonary hypertension by suppressing translation of the iron-sulfur cluster assembly protein ISCU. The resulting lack of iron-sulfur clusters results in mitochondrial dysfunction. We hypothesize that chronic intrauterine hypoxia leads to pulmonary hypertension by activation of the HIF-1? → miR210 → ISCU axis, resulting in increased mitochondrial-derived reactive oxygen species that lead to BKCa channel dysfunction. We propose three specific aims. Each specific aim is designed to integrate in vitro and in vivo approaches in order to better ascertain the relevance of the in vitro results to pulmonary function of the intact animal. Aim 1 will focus on determining the mechanism underlying BKCa channel dysfunction, and on establishing whether loss of BKCa channel function alone is adequate to result in pulmonary hypertension in intact lambs. Aim 2 will focus on the effects of hypoxia-induced increases in miR210 on ISCU activity, iron-sulfur cluster levels, and mitochondrial function and reactive oxygen species production. In intact lambs, we will establish whether activation of this pathway in the absence of hypoxia results in pulmonary hypertension, and whether suppression of this pathway in the presence of hypoxia prevents BKCa channel function and pulmonary hypertension. Aim 3 will investigate whether the increased reactive oxygen species levels in response to chronic hypoxia play a causative role in BKCa channel function and pulmonary hypertension. Using both in vitro and in vivo methods, we will determine whether the global antioxidant Vitamin C or mitochondria-specific antioxidant MitoQ will prevent pulmonary hypertension caused by chronic intrauterine hypoxia.

项目摘要 慢性宫内缺氧不仅在世界上1.4亿人中很常见， 世界上生活在高海拔地区，但也在许多并发症的怀孕，如先兆子痫， 吸烟和胎盘功能不全胎儿对慢性缺氧的适应 在许多不利的发展结果，包括新生儿的肺动脉高压。 BKCa通道对新生儿肺血管舒张至关重要， 出生最近的结果，从我们完善的胎羊模型的慢性缺氧， 妊娠表明BKCa通道功能障碍是肺动脉高压的一个致病因素。的 这项工作将探讨细胞缺氧和BKCa之间的机制联系 通道功能障碍其他人最近的研究表明，“主hypoxamir”miR 210， 微RNA被HIF-1？上调，通过抑制肺动脉高压 铁硫簇组装蛋白ISCU的翻译。由此导致的铁硫缺乏 簇导致线粒体功能障碍。我们假设慢性宫内缺氧 通过激活HIF-1导致肺动脉高压？→ miR 210 → ISCU轴， 导致尿道衍生的活性氧增加，导致BKCa通道 功能障碍 我们提出三个具体目标。每一个特定的目标都是为了在体外和体内整合 体内方法，以便更好地确定体外结果与肺 完整动物的功能。目标1将侧重于确定BKCa的潜在机制 通道功能障碍，并确定是否BKCa通道功能丧失单独 足以导致完整羔羊的肺动脉高压。目标2将侧重于以下方面的影响： 缺氧诱导的miR 210对ISCU活性、铁硫簇水平和 线粒体功能和活性氧的产生。在完整的羔羊，我们将 确定在缺氧不存在的情况下激活该途径是否会导致肺动脉高压。 高血压，以及在缺氧存在下抑制该通路是否会阻止BKCa 通道功能和肺动脉高压。目标3将调查是否增加了 慢性缺氧时的活性氧水平在BKCa中起致病作用 通道功能和肺动脉高压。使用体外和体内方法，我们将 确定全球抗氧化剂维生素C或特定的抗氧化剂MitoQ 可预防慢性宫内缺氧引起的肺动脉高压。