GATA-6 in pulmonary arterial hypertension

肺动脉高压(PAH)是一种危及生命的疾病，其特征是 肺血管阻力导致右心衰竭和死亡。尽管最近治疗方法发生了变化 范例，没有根治的治疗选择，目前可用的治疗方法不能逆转肺 血管重塑和/或阻止疾病进展。推进管理，提高工作成效 PAH患者，迫切需要新的分子靶点进行重塑治疗 干预措施。在已建立的PAH中，促进了PA血管平滑肌(PAVSMC)的生长和存活 内皮细胞(PAEC)的过度增殖都有助于小PA管腔的闭塞， 肺血管重构与肺动脉高压。因此，共享的信号分子选择性地调节过度兴奋。 PAEC和PAVSMC的增殖是多细胞重塑的理想靶点 治疗性干预。我们已发表的和初步的数据有力地表明转录缺陷 GATA6因子是人PAH和实验性PH中PAEC和PAVSMC的共同病理特征。 它负责维持过度增殖的细胞表型，肺血管重塑 和肺动脉高压(PH)。具体地说，我们发现GATA6在功能上是通过双向连接的。 调控血管内稳态、生长抑制BMP10/BMPRII的两个关键通路的定向串扰 和促增殖/促生存的YAP，并支持几种抗氧化酶的表达和活性 包括超氧化物歧化酶2(SOD2)。此外，我们还证明了内皮特异性GATA6缺陷 促进PAVSMC GATA6缺失和过度增殖，诱导PA肌化和自发性 小鼠的PH值。最后，我们发现靶向GATA6信号可以减少人PAH的过度增殖 EC特异性GATA6缺乏症小鼠的肺血管细胞和反向肺高压。基于已发布的和 新的初步数据，我们假设在远端PAEC和PAVSMC中需要GATA6缺陷 维持高增殖的细胞表型，小PA和整体PH的重塑。我们也 认为GATA6缺失由YAP激活、BMPRII缺陷和PAEC-PAVSMC支持 沟通，进而通过激活YAP，BMPRII，加剧肺血管重构 SOD2的缺失和下调。最后，我们提出，GATA6信号的恢复将选择性地 靶向高增殖的PAEC和PAVSMC，逆转或减弱肺血管重构和整体 pH值为了验证我们的假设，我们将：(1)机械地研究GATA6的作用和功能意义 人PAH、PAEC和PAVSMC的缺失；(2)确定GATA6缺失在PAEC-PAVSMC中的作用 相互作用；(3)评估GATA6的治疗靶向是否会逆转或减弱肺血管 临床前肺高压啮齿动物模型的重塑和整体肺高压。拟议的研究将确定新的关键 并为治疗干预寻找新的重要分子靶点。

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. Despite recent changes in treatment paradigms, there is no curative therapeutic options, and currently available therapies do not reverse pulmonary vascular remodeling and/or stop disease progression. To advance the management and improve outcomes of PAH patients, there is a significant need in new molecular targets for remodeling-focused therapeutic interventions. In established PAH, enhanced growth and survival of PA vascular smooth muscle (PAVSMC) and hyper-proliferation of endothelial cells (PAEC) both contribute to obliteration of the lumen of small PAs, pulmonary vascular remodeling and PAH. Thus, shared signaling molecules that selectively regulate hyper- proliferation of both, PAEC and PAVSMC, represent desirable targets for multi-cellular remodeling-focused therapeutic intervention. Our published and preliminary data strongly suggest that deficiency of transcription factor GATA6 is a shared pathological feature of PAEC and PAVSMC in human PAH and experimental PH, which is responsible for maintenance of hyper-proliferative cellular phenotypes, pulmonary vascular remodeling and pulmonary hypertension (PH). Specifically, we found that GATA6 is functionally connected via the bi- directional cross-talk to two key pathways regulating vascular homeostasis, growth-suppressing BMP10/BMPRII and pro-proliferative/pro-survival YAP, and supports expression and activity of several anti-oxidant enzymes including superoxide dismutase 2 (SOD2). Further, we demonstrate that endothelial-specific GATA6 deficiency promotes GATA6 loss and hyper-proliferation of PAVSMC and induces PA muscularization and spontaneous PH in mice. Lastly, we show that targeting GATA6 signaling reduces hyper-proliferation of human PAH pulmonary vascular cells and reverse PH in mice with EC-specific Gata6 deficiency. Based on published and new preliminary data, we hypothesize that GATA6 deficiency in distal PAEC and PAVSMC is required for maintenance of hyper-proliferative cellular phenotypes, remodeling of small PAs and overall PH. We also propose that GATA6 loss is supported by activation of Yap, BMPRII deficiency, and PAEC-PAVSMC communication, and, in turn, exacerbates pulmonary vascular remodeling by enabling Yap activation, BMPRII deficiency, and down-regulation of SOD2. Lastly, we propose that restoration of GATA6 signaling will selectively target hyper-proliferative PAEC and PAVSMC, reverse or attenuate pulmonary vascular remodeling and overall PH. To test our hypotheses, we will: (1) mechanistically investigate the role and functional significance of GATA6 deficiency in human PAH PAEC and PAVSMC; (2) determine the role of GATA6 loss in PAEC-PAVSMC interactions; (3) evaluate whether therapeutic targeting of GATA6 will reverse or attenuate pulmonary vascular remodeling and overall PH in preclinical rodent models of PH. The proposed study will identify new critical mechanisms and dissect new important molecular target for therapeutic intervention.