Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells.
Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells.
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DOI：
10.1152/ajplung.00097.2014
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
S. Wedgwood;S. Lakshminrusimha;P. Schumacker;R. Steinhorn
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文献类型：
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作者：
S. Wedgwood;S. Lakshminrusimha;P. Schumacker;R. Steinhorn
本研究旨在确定周期性牵张是否诱导对照肺动脉平滑肌细胞（PASMC）中NADPH氧化酶（Nox）4信号转导增加的新生儿持续性肺动脉高压（PPHN）表型，并确定参与的信号转导分子。为了实现这一点，PPHN诱导羔羊产前结扎动脉导管在妊娠128天。9天后，从对照（双胞胎）和PPHN羔羊分离肺和PASMC。对照PASMC暴露于1Hz和15%伸长率的循环拉伸24 h。通过抑制线粒体复合物III和NF-κB减弱牵张诱导的Nox 4表达，通过抑制Nox 4小干扰RNA和复合物III减弱牵张诱导的蛋白硫醇氧化。NF-κB活性在复合物III依赖性方式中通过牵张增加，并且牵张诱导的细胞周期蛋白D1表达通过复合物III抑制和Nox 4小干扰RNA减弱。这是第一项研究表明，周期性牵张通过线粒体复合物III诱导的胎儿PASMC NF-κB活化增加Nox 4表达，导致ROS信号传导和细胞周期蛋白D1表达增加。靶向这些信号分子可能会减弱与PPHN相关的肺血管重塑。
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.