Metabolic Reprogramming and Pulmonary Vascular Disease in Congenital Heart Disease

节目概要 肺血管疾病（pulmonary vascular disease，PVD）可能是先天性心脏病患儿最重要的并发症 导致肺血流量（PBF）和压力增加的疾病（CHD）。出生后， 心室水平（如室间隔缺损）或大血管水平（如动脉干）的大交通 动脉）使肺循环暴露于血流和压力的异常升高，这导致 肺血管结构和功能的进行性异常。代谢重编程是 越来越多地被认为是早期肺血管损伤和疾病的关键组成部分。血管 在我们的分流羔羊模型中的形态学研究表明，在分流中肺小动脉增加>2倍。 与对照组相比。这与在患有糖尿病的人中显示的动脉计数减少相反。 晚期疾病这种早期血管生成的增加可能代表了对血流增加的适应。 和压力过度增殖、抗凋亡的内皮细胞表型的发展对此是必要的 血管生成反应此外，它需要一个戏剧性的代谢重新编程，以提供这些细胞 与细胞分裂所需的必要的生物合成前体，同时减少细胞分裂， 由于消耗增加和呼吸减少导致ATP水平下降。我们将ATP的减少与 热休克蛋白90介导的NO信号的丢失和内皮功能障碍和血管内皮细胞的发展， 重塑因此，本PPG强烈关注增加我们对以下方面的理解：i） 对细胞代谢程序的机械力; ii）影响细胞代谢程序的翻译后修饰（PTM）; 参与代谢重编程的关键信号通路; iii）线粒体网络之间的相互作用 动力学、代谢和细胞存活; iv）这些途径如何相互作用以破坏hsp 90介导的NO 信号传导;和v）用于治疗具有增加的PBF的CHD的新的治疗策略。关键的新途径， 包括每个项目的重点是通过我们对代谢的深入研究确定的。 肺血管疾病发展的潜在重编程，并选择其能力， 有助于与β-氨基醇解和有氧糖酵解相关的细胞反应谱（项目#1）， 细胞氧化和线粒体生物能量学（项目#2），线粒体网络动力学和 线粒体自噬（项目#3）和细胞增殖和凋亡（项目#1和#3）。综合调查 在我们的三个PPG项目中，充分了解代谢重编程如何导致hsp 90的丢失， 介导的NO信号传导，并代表了这个PPG的主题基础。协同作用来自于 通过我们的计划方法，单个项目和科学核心之间的相互作用将促进 增加对机械力如何改变细胞代谢、NO信号传导和内皮细胞的理解， 功能，以及开发新的，个性化的治疗方法，以减轻肺血管疾病， 先天性心脏病导致PBF和压力增加的儿童。

PROGRAM SUMMARY Pulmonary vascular disease (PVD) is perhaps the most important complication for children with congenital heart disease (CHD) that results in increased pulmonary blood flow (PBF) and pressure. Postnatally, the presence of large communications at the level of the ventricles (e.g. ventricular septal defect) or great vessels (e.g. truncus arteriosus) exposes the pulmonary circulation to abnormal elevations in blood flow and pressure, which results in progressive structural and functional abnormalities of the pulmonary vasculature. Metabolic reprogramming is increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular morphology studies in our Shunt lamb model demonstrate a >2-fold increase in pulmonary arterioles in Shunt compared to control lambs. This is opposed to the decrease in arterial counts demonstrated in humans with advanced disease. This early increase in angiogenesis likely represents an adaptation to the increase in flow and pressure. The development of a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this angiogenic response. Further, it requires a dramatic metabolic reprogramming that serves to supply these cells with the necessary biosynthetic precursors required for cell division while simultaneously decreasing cellular ATP levels due to increased consumption and decreased respiration. We have linked this decrease in ATP to the loss of hsp90-mediated NO signaling and the development of endothelial dysfunction and vascular remodeling. Thus, this PPG intensely focuses on increasing our understanding of: i) the differential effects of mechanical forces on cellular metabolic programming; ii) post translational modifications (PTMs) that influence key signaling pathways involved in metabolic reprogramming; iii) interactions between mitochondrial network dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. The key novel pathways that comprise the focus of each Project were identified by our intensive investigations into the metabolic reprogramming underlying the development of pulmonary vascular disease and selected for their capacity to contribute to a spectrum of cellular responses related to glutaminolysis and aerobic glycolysis (Project #1), cellular ß-oxidation and mitochondrial bioenergetics (Project #2), mitochondrial network dynamics and mitophagy (Project #3), and cell proliferation and apoptosis (Projects #1 & #3). Investigations are integrated across our three PPG projects to fully understand how metabolic reprogramming leads to the loss of hsp90- mediated NO signaling and represents the thematic underpinning of this PPG. The synergy derived from the interactions between individual Projects and scientific Cores, with our programmatic approaches, will promote an increased understanding of how mechanical forces modify cell metabolism, NO signaling and endothelial function, and the development of novel, individualized therapies to attenuate pulmonary vascular disease in children born with CHD that result in increased PBF and pressure.