Impact of Prenatal Hypoxia on Mitochondrial Function of Offspring Hearts

产前缺氧对子代心脏线粒体功能的影响

• 批准号: 9483752
• 负责人: LOREN P THOMPSON
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9483752
• 关键词: Acute; Adult; Affect; Air; Animal Model; Animals; Antioxidants; Arteries; Biological Sciences; Cardiac; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Cavia; Cell Survival; Cells; Chronic; Clinical; Complex; Consumption; DNA Methylation; DNA Methylation Regulation; Data; Defect; Discipline of obstetrics; Echocardiography; Economic Burden; Electron Transport; Environment; Epidemiology; Epigallocatechin Gallate; Epigenetic Process; Equus caballus; Exhibits; Exposure to; Fatty Acids; Fetal Growth; Fetal Growth Retardation; Fetal Heart; Fetus; Fibrinogen; Functional disorder; Gene Expression; Genes; Genus Hippocampus; Goals; Growth; Heart; Heart Diseases; Heart failure; High Fat Diet; Hypoxemia; Hypoxia; Impairment; In Vitro; Inflammation; Knowledge; Lead; Link; Lipid Peroxidation; Long-Term Effects; Matrix Metalloproteinases; Measures; Mediating; Messenger RNA; Metabolic; Methods; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Morbidity - disease rate; Myocardial dysfunction; Nitric Oxide Synthase; Nuclear; Organ; Outcome; Overnutrition; Oxidative Stress; Oxygen; Performance; Perinatal mortality demographics; Peroxonitrite; Pharmacotherapy; Phenotype; Physiological; Pre-Eclampsia; Pregnancy; Production; Publishing; Reflex action; Reporting; Respiration; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sea; Secondary to; Sex Characteristics; Site; Small Interfering RNA; Stress; Stress Tests; Structure; Testing; Toxin; Transfection; Western Blotting; age group; base; complex IV; critical period; effective therapy; enzyme activity; fetal; fetus hypoxia; heart function; heart metabolism; imaging modality; improved; in utero; in vivo; indexing; infant death; inhibitor/antagonist; maternal obesity; mitochondrial dysfunction; mitochondrial messenger RNA; mortality; neonate; nitrosative stress; non-invasive imaging; offspring; oxidative damage; perinatal morbidity; postnatal; pregnant; prenatal; prenatal exposure; pressure; prevent; protective effect; protein expression; public health relevance; reproductive; respiratory; response; stressor; translational impact; vasoconstriction

 DESCRIPTION (provided by applicant): Prenatal hypoxia is one of the most significant clinical challenges facing obstetrics today. Adverse in utero conditions that result in reduced oxygen delivery to the fetus generate fetal growth restriction associated with morbidity and mortality. Epidemiological and animal studies have convincingly shown that growth-restricted fetuses have an increased risk of adult cardiovascular disease. We have shown that prenatal hypoxia of pregnant guinea pigs generates a fetal cardiac phenotype of inflammation, oxidative and nitrosative stress, and altered mitochondrial enzyme activity. Further, the offspring exhibit reduced mitochondrial protein expression, mitochondrial respiration and cardiac performance. Mitochondria are important for energy production of the cardiac cell whose normal function is critical for cell survival. We hypothesize that intrauterine hypoxia permanently alters fetal cardic mitochondrial respiration via epigenetic mechanisms associated with DNA methylation, compromising heart function in the offspring. We will study the effects of prenatal hypoxia on 90d old guinea pig offspring and determine the programming effects on the 1) mitochondrial respiratory capacity, mRNA/protein expression, and DNA methylation of isolated cardiac cells of offspring hearts, 2) protective effects of prenatal treatment against nitrosative and oxidative stress on cardiac function of offspring hearts, and 3) the vulnerability of heart function to subsequent stressors via pressure overload and fatty acid excess. We will use state-of-the-art approaches for investigating epigenetic mechanisms (DNA methylation), mitochondrial respiration (Sea Horse Bioscience XF24 Analyzer) of freshly cardiac cells, and cardiac performance (non-invasive echocardiography) in guinea pig offspring exposed to normoxia and hypoxia in utero. Responses to subsequent physiological challenges such as aortic pressure overload and high fat diet will be measured to identify the translational impact of fetal hypoxemia on the vulnerability of offspring hearts to cardiac failure. This will bring a new perspective on te role of the mitochondrion as an important target site of oxidative damage in utero in contributing as a causative factor in cardiac dysfunction in the offspring.

 描述(由申请人提供)：产前缺氧是当今产科面临的最重大的临床挑战之一。不利的宫内条件会导致对胎儿的氧气输送减少，从而导致胎儿生长受限，从而导致发病率和死亡率。流行病学和动物研究令人信服地表明，生长受限的胎儿患成年心血管疾病的风险增加。我们已经证明，妊娠豚鼠出生前缺氧会产生炎症、氧化和亚硝酸应激的胎儿心脏表型，并改变线粒体酶活性。此外，后代表现出线粒体蛋白表达、线粒体呼吸和心脏功能的减少。线粒体对心肌细胞的能量生产是重要的，而心肌细胞的正常功能对细胞的生存至关重要。我们假设宫内缺氧通过与DNA甲基化相关的表观遗传机制永久性地改变胎儿的心脏线粒体呼吸，损害后代的心脏功能。我们将研究产前缺氧对90d龄豚鼠后代的影响，并确定其对1)子代心脏线粒体呼吸能力、mRNA/蛋白质表达和DNA甲基化的编程效应，2)产前治疗对子代心脏亚硝酸盐和氧化应激的保护作用，以及3)心功能对随后压力超负荷和脂肪酸过量应激源的易感性。我们将使用最先进的方法来研究新鲜心肌细胞的表观遗传机制(DNA甲基化)、线粒体呼吸(海马生物科学XF24分析仪)以及暴露在宫内常氧和低氧下的豚鼠后代的心脏表现(无创超声心动图)。将测量对后续生理挑战的反应，如主动脉压力超负荷和高脂肪饮食，以确定胎儿低氧血症对翻译的影响。 关于子代心脏对心力衰竭的脆弱性。这将为线粒体作为子宫内氧化损伤的重要靶点在子代心脏功能障碍的致病因素中的作用带来新的视角。