Wedgwood Stephen, Lakshminrusimha Satyan, Schumacker Paul T, Steinhorn Robin H
Department of Pediatrics, University of California Davis Medical Center, Sacramento, California;
Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York; and.
Am J Physiol Lung Cell Mol Physiol. 2015 Jul 15;309(2):L196-203. doi: 10.1152/ajplung.00097.2014. Epub 2015 May 29.
This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-κB, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-κB activity was increased by stretch in a complex III-dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III-induced activation of NF-κB in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN.
本研究旨在确定周期性牵张是否会在对照肺动脉平滑肌细胞（PASMC）中诱导出具有增加的烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox）4信号的新生儿持续性肺动脉高压（PPHN）表型，并确定其中涉及的信号转导分子。为实现这一目标，在妊娠128天时通过产前结扎动脉导管在羔羊中诱导出PPHN。9天后，从对照（双胞胎）和PPHN羔羊中分离出肺和PASMC。将对照PASMC暴露于1Hz和15%伸长率的周期性牵张下24小时。线粒体复合物III和NF-κB的抑制减弱了牵张诱导的Nox4表达，Nox4小干扰RNA和复合物III抑制减弱了牵张诱导的蛋白质硫醇氧化。牵张以复合物III依赖性方式增加NF-κB活性，复合物III抑制和Nox4小干扰RNA减弱了牵张诱导的细胞周期蛋白D1表达。这是第一项表明周期性牵张通过线粒体复合物III诱导胎儿PASMC中NF-κB激活来增加Nox4表达，从而导致活性氧信号传导和细胞周期蛋白D1表达增加的研究。靶向这些信号分子可能会减弱与PPHN相关的肺血管重塑。
