miR-223 reverses experimental pulmonary arterial hypertension
miR-223 reverses experimental pulmonary arterial hypertension
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DOI：
10.1152/ajpcell.00149.2015
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发表时间：
2015-09-15
影响因子：
5.5
通讯作者：
Bonnet, Sebastien
中科院分区：
文献类型：
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作者：
Meloche, Jolyane;Le Guen, Marie;Bonnet, Sebastien
肺动脉高压（PAH）是一种影响肺血管系统的毁灭性疾病。肺动脉阻塞是由于血管壁内肺动脉平滑肌细胞（PASMCs）增殖增加和细胞凋亡抑制。最近的研究表明，DNA损伤可以通过上调聚（adp -核糖）聚合酶1 （PARP-1）的表达来触发这种表型，尽管确切的机制尚不清楚。计算机分析和癌症研究表明microRNA miR-223靶向PARP-1。因此，我们假设miR-223下调触发PARP-1过表达，以及在PAH中观察到的增殖/凋亡失衡。我们提供的证据表明，miR-223在人类多环芳烃肺、远端PAs和分离的pasmc中下调。此外，通过功能的获得和丧失方法，我们发现在PAH中观察到的缺氧诱导因子1 α的增加触发了miR-223表达的降低和随后PARP-1的过表达，从而允许PAH- pasmc增殖和抵抗凋亡。最后，我们证明了恢复miR-223在单罗塔林诱导的多环芳烃大鼠肺中的表达可以逆转已建立的多环芳烃，并对血管重塑、肺阻力、右心室肥厚和生存产生有益影响。我们提供的证据表明，miR-223在PAH中下调在与疾病相关的许多途径中发挥重要作用，恢复其表达能够逆转PAH。
Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose) polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1 alpha, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.