Role of altered carnitine metabolism in perinatal endothelial dysfunction

描述(由申请人提供)：大约1%的儿童出生时患有先天性心脏缺陷，其中一半需要内科和/或外科治疗。虽然这些儿童的存活率有所提高，但他们的发病率和晚期死亡率仍然很高。这是因为他们患肺血管疾病的风险很大。事实上，即使是早期的肺内皮细胞功能障碍，伴随着异常的血管反应性，也会导致显著的发病率和死亡率。我们最近利用先天性心脏病和肺血流增加的羔羊模型进行的研究表明，内皮功能障碍的发展与NO信号的紊乱有关。然而，内皮功能障碍的发生机制尚未得到充分解决。最近我们发现，NO信号的减少与肉碱代谢的改变和线粒体功能障碍有关。因此，这项建议的目的有两个：1)利用综合的生理学、生化、细胞和分子方法来阐明肉碱在我们的羔羊模型中代谢紊乱的机制；以及2)以一种新颖和创新的方式利用L-卡尼汀作为一种治疗先天性心脏病相关的内皮功能障碍的药物。因此，我们预计，从这项探索性R21建议的研究中获得的信息将使我们能够检查线粒体功能障碍在先天性心脏病相关血管反应性改变中所起的作用，并评估L-卡尼汀作为一种新的治疗策略。在美国，先天性心脏病的发病率约为每100名活产儿中就有一名。这些儿童中约有50%需要内科和/或外科治疗。大多数需要治疗的缺陷与肺血流增加有关。这包括出生时患有室间隔缺陷、动脉干或房室间隔缺陷的儿童。由于新的诊断工具的发展，以及外科技术和术后管理的进步，出生时患有先天性心脏病的儿童的存活率得到了改善。然而，这些儿童继续遭受严重的发病率和晚期死亡率，部分原因是血管反应异常导致肺循环内皮细胞功能障碍。与公共卫生相关：导致内皮功能障碍的因素还不完全清楚。更好地了解内皮功能障碍发生的细胞和分子机制将有助于提高新生儿、婴儿和先天性心脏病儿童的存活率。因此，这项提案中的研究评估了一种化合物L-卡尼汀，这种化合物几十年来一直被用于治疗先天性代谢错误，作为一种治疗肺血流量增加的肺高压的新颖创新疗法，有可能显著影响出生时患有先天性心脏病的儿童的存活率。

DESCRIPTION (provided by applicant): Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Our recent studies, using a lamb model of congenital heart disease and increased pulmonary blood flow, indicate that the development of endothelial dysfunction is associated with derangements in NO signaling. However, the mechanisms by which the endothelial dysfunction occurs have not been adequately resolved. Recently we have found that decreases in NO signaling correlate with altered carnitine metabolism and mitochondrial dysfunction. Thus, the Aims of this proposal are two-fold: 1) To utilize an integrated physiologic, biochemical, cellular, and molecular approach to elucidate the mechanisms underlying the disruption of carnitine metabolism in our lamb model; and 2) To utilize L-carnitine, a compound that has been used for decades to treat inborn errors of metabolism, in a novel and innovative way as a therapeutic agent for the endothelial dysfunction associated with congenital heart disease. Thus, we anticipate that the information garnered from the studies in this exploratory R21 proposal should enable us both to examine the role played by mitochondrial dysfunction in the altered vascular reactivity associated with congenital heart disease and to evaluate L-carnitine as a novel treatment strategy. The incidence of congenital heart defects in the U.S. is ~1 per 100 live births. Approximately 50% of these children require medical and/or surgical attention. The majority of defects requiring treatment are associated with increased pulmonary blood flow. This includes children born with ventricular septal defect, truncus arteriosus, or atrioventricular septal defect. Survival for children born with congenital heart defects has improved because of the development of new diagnostic tools, and advances in surgical techniques and post-operative management. However, these children continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity leading to endothelial dysfunction within the pulmonary circulation. PUBLIC HEALTH RELEVANCE: The factors responsible for the development of endothelial dysfunction are incompletely understood. A better understanding of the cellular and molecular mechanisms that underlie the development of endothelial dysfunction will lead to improved survival for newborns, infants, and children with congenital heart defects. Thus, the studies in this proposal evaluating a compound, L-Carnitine that has been utilized for decades to treat inborn errors of metabolism as a novel and innovative therapy for pulmonary hypertension associated with increased pulmonary blood flow have the potential to significantly impact the survival of children born with congenital heart defects.