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: 10218255
• 负责人: LOREN P THOMPSON
• 金额: $ 52.92万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218255
• 关键词: ATP Synthesis Pathway; Adenine Nucleotides; Adult; Adult Children; Adverse event; Affect; Aging; Apoptosis; Attention; Bioenergetics; Biogenesis; Blood Vessels; Cardiac; Cardiovascular Physiology; Cause of Death; Cavia; Cell membrane; Cells; Characteristics; Chronic; Complex; Confocal Microscopy; Consumption; Data; Deterioration; Development; Disease; Echocardiography; Energy Metabolism; Equilibrium; Ethnic group; Etiology; Exhibits; Exposure to; Face; Failure; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Heart; Fetus; Functional disorder; Gene Expression; Generations; Glycolysis; Goals; Growth; Growth and Development function; Health; Health Care Costs; Heart; Heart Diseases; Heart Mitochondria; Heart Ventricle; Heart failure; Hypertension; Hypoxemia; Hypoxia; Image; Impairment; Inflammation; Knowledge; Life; Link; Measures; Membrane; Membrane Potentials; Messenger RNA; Metabolic syndrome; Mitochondria; Mitochondrial Proteins; Molecular Target; Morphology; Myocardial dysfunction; NADH; Niacinamide; Organ; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; PPAR Pathway; Pathology; Pathway interactions; Pharmacology; Pharmacotherapy; Phase; Phenotype; Play; Pregnancy; Premature aging syndrome; Prenatal care; Process; Regulation; Research; Resolution; Respiration; Respiratory Chain; Respiratory physiology; Resveratrol; Risk; Role; Signal Transduction; Sirtuins; Stimulus; Stress; Stroke; Structure; Suggestion; Transcriptional Regulation; Treatment Protocols; Ventricular Dysfunction; Ventricular Function; Woman; cardioprotection; complex IV; cytochrome c oxidase; disorder risk; fatty acid oxidation; fetal; heart cell; heart disease risk; heart function; improved; in utero; in vivo; intrauterine environment; live cell imaging; men; mitochondrial dysfunction; mitochondrial membrane; mortality risk; neonate; nicotinamide-beta-riboside; novel strategies; offspring; perinatal period; porcine model; postnatal; pregnant; prenatal; prenatal exposure; pressure; prevent; programs; protein expression; public health relevance; respiratory; response; sexual dimorphism

Project Summary Adverse events occurring during fetal life can contribute to an increased risk of disease in adult life. Chronic intrauterine hypoxia causes fetal growth restriction and renders the offspring vulnerable to hypertension and heart disease as well as other complications. Thus, the developmental origins of health and disease (DOHaD) hypothesis has posited a critical role of prenatal care in etiologies of several disease conditions. Prenatal hypoxia has been shown to disrupt cardiovascular function through mechanisms associated with both heart and blood vessel pathologies. We have generated a well established hypoxic pregnant guinea pig model that exhibits fetal and offspring phenotype of mitochondrial dysfunction. Further, our data show that exposure to hypoxia during the fetal growth phase inhibits contractile function in the offspring heart. We propose that mitochondrial-specific mechanisms associated with biogenesis and bioenergetics in the fetal heart are inhibited, which is sustained in the offspring and manifest as cardiac ventricular dysfunction. We will determine the effects of prenatal hypoxia on mRNA/gene expression of the PGC1a/PPAR pathway and respiratory chain complex expression in fetal hearts. We will evaluate the sustained consequences of prenatal hypoxia on mitochondrial respiration in intact cardiac cells. Using live cell imaging with super-resolution confocal microscopy, we will identify the effects of prenatal hypoxia on mitochondrial structure, membrane integrity, and Ca2+ transients in cell contraction of cardiac cells from offspring hearts. We will evaluate ventricular dysfunction in the offspring hearts exposed to prenatal hypoxia by echocardiography and pressure-volume loop analysis. Finally, we will treat pregnant sows and neonates with nicotinamide modulators (resveratrol and nicotinamide riboside) to enhance the NAD+/NADH ratio, which is a central regulator of energy metabolism. We will determine whether treatment enhances mitochondrial function and/or contractile function of the offspring as a pharmacological approach for improving mitochondrial health and reducing the risk of heart disease.

项目摘要 胎儿期发生的不良事件可能导致成年期疾病风险增加。慢性宫内 缺氧导致胎儿生长受限，使后代易患高血压和心脏病， 其他并发症。因此，健康和疾病的发展起源（DOHaD）假说提出了一个关键的 产前护理在几种疾病病因学中的作用。产前缺氧会破坏 心血管功能通过与心脏和血管病理相关的机制。我们已经生成 一个良好建立的缺氧妊娠豚鼠模型，显示胎儿和后代的线粒体表型 功能障碍此外，我们的数据表明，在胎儿生长阶段暴露于缺氧抑制了心脏的收缩功能， 孩子的心。我们认为，与生物起源和生物能量学相关的特定机制， 胎儿心脏受到抑制，这在后代中持续并表现为心室功能障碍。我们将 确定产前缺氧对PGC 1a/PPAR途径和呼吸链的mRNA/基因表达的影响 复杂的表达。我们将评估产前缺氧对线粒体的持续影响， 完整心肌细胞的呼吸。使用活细胞成像与超分辨率共聚焦显微镜，我们将确定 产前缺氧对线粒体结构、膜完整性和细胞收缩中Ca 2+瞬变的影响 从后代心脏中提取心脏细胞。我们将评估胎儿心脏暴露在产前心室功能障碍 通过超声心动图和压力-容积环分析来检测缺氧。最后，我们将用以下药物治疗妊娠母猪和新生母猪： 烟酰胺调节剂（白藜芦醇和烟酰胺核苷），以提高NAD+/NADH的比例，这是一个中心的 能量代谢的调节剂。我们将确定治疗是否能增强线粒体功能和/或收缩功能， 作为改善线粒体健康和降低心脏病风险的药理学方法， 疾病