Impact of Prenatal Hypoxia on Mitochondrial Function of Offspring Hearts

项目摘要 胎儿时期发生的不良事件可能会增加成年后患病的风险。慢性宫内 缺氧会导致胎儿生长受限，并使后代容易患高血压和心脏病 其他并发症。因此，健康与疾病的发育起源(DOHAD)假说提出了一个关键的 产前护理在几种疾病病因中的作用。已有研究表明，产前缺氧会扰乱 通过与心脏和血管病理相关的机制发挥心血管功能。我们已经产生了 一种已建立的具有胎儿和子代线粒体表型的低氧妊娠豚鼠模型 功能障碍。此外，我们的数据显示，在胎儿生长阶段暴露在低氧环境中会抑制心脏的收缩功能。 后代的心脏。我们认为线粒体特有的机制与生物发生和生物能量学有关。 胎儿心脏受到抑制，在后代中持续存在，表现为心室性功能障碍。我们会 产前低氧对胎鼠PGC1a/PPAR途径及呼吸链基因和mRNA表达的影响 胎儿心脏的复杂表达。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作用。使用超分辨率共聚焦显微镜的活细胞成像，我们将识别 产前低氧对大鼠心肌细胞收缩过程中线粒体结构、膜完整性和钙瞬变的影响 来自子代心脏的心脏细胞。我们将评估出生前暴露于心脏的子代的心功能障碍 超声心动图和压力-容量环分析缺氧。最后，我们将对怀孕母猪和新生儿进行治疗 烟酰胺调节剂(白藜芦醇和烟酰胺核苷)提高NAD+/NADH比率，这是一个中心 能量代谢调节剂。我们将确定治疗是否增强线粒体功能和/或收缩 子代的功能作为改善线粒体健康和降低心脏风险的药理学方法 疾病。

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.