Perinatal NO signaling in congenital heart disease

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 手术治疗先天性心脏病导致PBF增加的儿童发育异常 肺血管反应性虽然这些儿童的生存状况有所改善，但他们仍在受苦。 发病率和晚期死亡率。这是因为他们有很大的风险发展肺血管 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， 严重的发病率和死亡率。使用实验性羔羊CHD模型，增加PBF（分流）， 是第一个发现热休克蛋白90（hsp 90）和内皮NO之间相互作用减少的人。 一氧化氮合酶（eNOS）在与该疾病相关的减少的一氧化氮（NO）信号传导中起主要作用。 我们的数据表明，在这个过程中，热休克蛋白90的活性下降，以及eNOS硝化的增加。在 此外，我们发表的数据表明，热休克蛋白90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硝化破坏了其 与hsp 90的相互作用导致二聚体破坏和NO生成减少。此外，我们将调查，如果 刺激hsp 90活性将恢复NO信号传导和内皮功能。我们的调查将在 三个相互关联但又相互独立的目标。我们将采用一种转化方法， 生物物理、细胞和整个动物研究。我们的学业圆满完成， 机械的见解，并将确定新的目标，是服从治疗干预。

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.