Impact of Prenatal Hypoxia on Mitochondrial Function of Offspring Hearts

 描述（由申请人提供）：产前缺氧是当今产科面临的最重要的临床挑战之一。子宫内不良情况导致胎儿供氧减少，导致胎儿生长受限，并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，妊娠豚鼠产前缺氧产生的胎儿心脏表型的炎症，氧化和亚硝化应激，并改变线粒体酶活性。此外，后代表现出降低的线粒体蛋白质表达、线粒体呼吸和心脏性能。线粒体对于心脏细胞的能量产生是重要的，心脏细胞的正常功能对于细胞存活是至关重要的。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改变胎儿心脏线粒体呼吸，损害后代的心脏功能。我们将研究产前缺氧对90日龄豚鼠子代的影响，并确定对子代心脏分离心肌细胞线粒体呼吸能力、mRNA/蛋白质表达和DNA甲基化的编程影响，2）产前处理对亚硝化和氧化应激对子代心脏心功能的保护作用，以及3）心脏功能对随后的压力超负荷和脂肪酸过量的应激源的脆弱性。我们将使用最先进的方法来研究表观遗传机制（DNA甲基化），新鲜心脏细胞的线粒体呼吸（海马生物科学XF 24分析仪），以及暴露于宫内常氧和缺氧的豚鼠后代的心脏性能（无创超声心动图）。对随后的生理挑战，如主动脉压超负荷和高脂肪饮食的反应将被测量，以确定胎儿低氧血症的转化影响 关于后代心脏对心力衰竭的脆弱性。这将带来一个新的视角的作用，作为一个重要的目标网站的氧化损伤在子宫内的贡献作为一个致病因素，在后代的心功能障碍。

 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.