Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats
Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats
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DOI：
10.1038/pr.2013.42
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发表时间：
2013-06-01
影响因子：
3.6
通讯作者：
Wu, Shu
中科院分区：
文献类型：
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作者：
Alapati, Deepthi;Rong, Min;Wu, Shu
背景：高氧诱导的新生儿肺损伤与Wnt/β-连环蛋白信号通路的激活有关。低密度脂蛋白受体相关蛋白5和6（LRP 5/6）是与Wnt配体结合并介导经典Wnt/β-连环蛋白信号传导的Wnt辅助受体。我们假设LRP 5/6的通用抑制剂Mesd抑制LRP 5/6，将减轻高氧诱导的肺损伤.METHODS：新生大鼠幼崽随机暴露于常氧或高氧90%FiO（2），并腹腔注射安慰剂或Mesd，每隔一天，共14天。在第15天，检测LRP 5/6（pLRP 5/6）的磷酸化、Wnt/β-连环蛋白靶基因、细胞周期蛋白D1和Wnt诱导的信号蛋白-1（WISP-1）的表达、右心室收缩压（RVSP）、右心室肥大（RVH）、肺血管重构、肺泡化和血管化。高氧暴露显著诱导pLRP 5/6、细胞周期蛋白D1和WISP-1在安慰剂动物的肺中的表达，但是它们被施用Mesd显著减弱。Mesd还显著减弱高氧诱导的肺动脉高压（PH）和肺血管重构。然而，有没有影响肺泡化或血管化后Mesdadministration.CONCLUSION：这项研究表明，LRP 5/6介导肺血管重塑和PH在高氧诱导的新生儿肺损伤，从而提出了一个潜在的治疗目标，以减轻PH在新生儿严重支气管肺发育不良。
BACKGROUND: Hyperoxia-induced neonatal lung injury is associated with activation of Wnt/beta-catenin signaling. Low-density lipoprotein receptor related proteins 5 and 6 (LRP5/6) are Wnt coreceptors that bind to Wnt ligands and mediate canonical Wnt/beta-catenin signaling. We hypothesized that inhibition of LRP5/6 by their universal inhibitor, Mesd, would attenuate hyperoxia-induced lung injury.METHODS: Newborn rat pups were randomly exposed to normoxia or hyperoxia at 90% FiO(2) and injected intraperitoneally with placebo or Mesd every other day for 14 d. On day 15, phosphorylation of LRP5/6 (pLRP5/6), expression of Wnt/beta-catenin target genes, cyclin D1 and Wnt-induced signaling protein-1 (WISP-1), right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), pulmonary vascular remodeling, alveolarization, and vascularization were measured.RESULTS: Hyperoxia exposure markedly induced pLRP5/6, cyclin D1, and WISP-1 expression in the lungs of placebo animals, but they were significantly attenuated by the administration of Mesd. Mesd also significantly attenuated hyperoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling. However, there was no effect on alveolarization or vascularization after Mesd administration.CONCLUSION:This study demonstrates that LRP5/6 mediates pulmonary vascular remodeling and PH in hyperoxia-induced neonatal lung injury, thereby suggesting a potential therapeutic target to alleviate PH in neonates with severe bronchopulmonary dysplasia.