Perinatal NO signaling in congenital heart disease

大约1%的儿童出生时就患有先天性心脏缺陷，其中一半需要医疗和/或 外科治疗。先天性心脏缺陷导致PBF增加的儿童发育异常 肺血管反应性。尽管这些儿童的存活率有所提高，但他们仍在遭受痛苦 发病率和晚期死亡率。这是因为他们有很大的发展肺血管的风险。 疾病。事实上，即使是早期的肺内皮功能障碍，伴随着异常的血管反应性，也会导致 严重的发病率和死亡率。利用实验性冠心病伴分流增加的羔羊模型 首次发现热休克蛋白90(HSP90)与内皮细胞NO之间的相互作用减少 一氧化氮合酶(ENOS)在一氧化氮(NO)信号转导途径中起重要作用。 我们的数据表明，在这一过程中，HSP90活性下降，eNOS硝化增加。在……里面 此外，我们公布的数据表明，HSP90活性的丧失与eNOS的破坏有关 二聚体结构。基于这些数据，我们将检验的总体假设是eNOS硝化作用破坏了其 与HSP90的相互作用导致二聚体的破坏，并减少NO的生成。此外，我们将调查是否 刺激HSP90活性将恢复NO信号和内皮功能。我们的调查将会进行 在三个相互关联但又相互独立的目标中。我们将利用一种翻译方法，将 生物物理学、细胞学和整体动物研究。我们顺利完成学业应该会产生新的成果 这是一种机械性的洞察力，并将确定可用于治疗干预的新靶点。

Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Children born with congenital heart defects that result in increased PBF develop abnormal pulmonary vascular reactivity. 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. Using an experimental lamb model of CHD with increased PBF (Shunt) we were the first to identify that decreased interactions between heat shock protein 90 (hsp90) and endothelial NO synthase (eNOS) plays a major role in the reduced nitric oxide (NO) signaling associated with this disease. Our data implicate decreases in hsp90 activity as well as an increase in eNOS nitration in this process. In addition, our published data indicate that the loss of hsp90 activity correlates with the disruption of the eNOS dimeric structure. Based on these data, the overall hypothesis we will test is that eNOS nitration disrupts its interaction with hsp90 leading to dimer disruption and decreased NO generation. Further, we will investigate if stimulating hsp90 activity will restore NO signaling and endothelial function. Our investigations will be carried out in three interrelated, but independent, Aims. We will utilize a translational approach that will integrate biophysical, cellular and whole animal studies. The successful completion of our studies should yield new mechanistic insights and will identify new targets that are amenable to therapeutic intervention.