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，其中一半需要医疗和/或手术治疗。虽然这些儿童的存活率有所提高，但他们仍然患有发病率和晚期死亡率。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功能障碍，伴有血管反应性异常，也会导致显著的发病率和死亡率。我们最近的研究，使用先天性心脏病羔羊模型和肺血流量增加，表明内皮功能障碍的发展与NO信号紊乱有关。然而，内皮功能障碍发生的机制尚未得到充分解决。最近我们发现一氧化氮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，本研究的目的有两个方面：1)利用综合的生理、生化、细胞和分子方法来阐明我们的羔羊模型中肉毒碱代谢中断的机制；2)利用几十年来一直用于治疗先天性代谢错误的化合物左旋肉碱，以一种新颖和创新的方式作为先天性心脏病相关内皮功能障碍的治疗剂。因此，我们预计，从这项探索性R21提案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与先天性心脏病相关的血管反应性改变中所起的作用，并评估左旋肉碱作为一种新的治疗策略。在美国，先天性心脏缺陷的发生率约为每100个活产婴儿中有1个。这些儿童中约有50%需要医疗和/或手术治疗。大多数需要治疗的缺陷与肺血流量增加有关。这包括先天性室间隔缺损、动脉干或房室间隔缺损的儿童。由于新的诊断工具的发展，以及手术技术和术后管理的进步，先天性心脏缺陷儿童的存活率有所提高。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性异常导致肺循环内内皮功能障碍。公共卫生相关性：导致内皮功能障碍的因素尚不完全清楚。更好地了解内皮功能障碍发展的细胞和分子机制将提高新生儿、婴儿和先天性心脏缺陷儿童的生存率。因此，本提案的研究评估了一种化合物，左旋肉碱，几十年来一直用于治疗先天性代谢错误，作为一种新的和创新的治疗肺动脉高压的方法，与肺血流量增加有关，有可能显著影响先天性心脏缺陷儿童的生存。

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.