Department of Pediatrics, School of Medicine, University of New Mexico, Albuquerque, 87131, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L872-80. doi: 10.1152/ajplung.00405.2010. Epub 2011 Sep 9.
Pulmonary hypertension occurs with prolonged exposure to chronic hypoxia in both adults and neonates. The Ca(2+)-dependent transcription factor, nuclear factor of activated T cells isoform c3 (NFATc3), has been implicated in chronic hypoxia-induced pulmonary arterial remodeling in adult mice. Therefore, we hypothesized that NFATc3 is required for chronic hypoxia-induced pulmonary hypertension in adult and neonatal mice. The aim of this study was to determine whether 1) NFATc3 mediates chronic hypoxia-induced increases in right ventricular systolic pressure in adult mice; 2) NFATc3 is activated in neonatal mice exposed to chronic hypoxia; and 3) NFATc3 is involved in chronic hypoxia-induced right ventricular hypertrophy and pulmonary vascular remodeling in neonatal mice. Adult mice were exposed to hypobaric hypoxia for 2, 7, and 21 days. Neonatal mouse pups were exposed for 7 days to hypobaric chronic hypoxia within 2 days after delivery. Hypoxia-induced increases in right ventricular systolic pressure were absent in NFATc3 knockout adult mice. In neonatal mice, chronic hypoxia caused NFAT activation in whole lung and nuclear accumulation of NFATc3 in both pulmonary vascular smooth muscle and endothelial cells. In addition, heterozygous NFATc3 neonates showed less right ventricular hypertrophy and pulmonary artery wall thickness in response to chronic hypoxia than did wild-type neonates. Our results suggest that NFATc3 mediates pulmonary hypertension and vascular remodeling in both adult and neonatal mice.
肺动脉高压发生在成人和新生儿长时间暴露于慢性缺氧环境中。钙依赖性转录因子活化 T 细胞核因子 c3（NFATc3）已被认为参与了成年小鼠慢性缺氧诱导的肺动脉重构。因此，我们假设 NFATc3 是成年和新生小鼠慢性缺氧诱导肺动脉高压所必需的。本研究旨在确定以下几点：1）NFATc3 是否介导成年小鼠慢性缺氧引起的右心室收缩压升高；2）NFATc3 在暴露于慢性缺氧的新生小鼠中是否被激活；3）NFATc3 是否参与了新生小鼠慢性缺氧诱导的右心室肥厚和肺血管重构。成年小鼠被暴露于低压缺氧环境中 2、7 和 21 天。新生小鼠在出生后 2 天内，被暴露于低压慢性缺氧中 7 天。NFATc3 敲除成年小鼠中，缺氧诱导的右心室收缩压升高现象消失。在新生小鼠中，慢性缺氧导致整个肺中的 NFAT 激活，以及肺动脉平滑肌和内皮细胞中 NFATc3 的核内积累。此外，杂合子 NFATc3 新生小鼠对慢性缺氧的反应性右心室肥厚和肺动脉壁厚度较野生型新生小鼠减少。我们的研究结果表明，NFATc3 介导了成年和新生小鼠的肺动脉高压和血管重构。
