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首页> 外文期刊>Pulmonary Circulation >Novel Signaling Pathways in Pulmonary Arterial Hypertension (2015 Grover Conference Series):
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Novel Signaling Pathways in Pulmonary Arterial Hypertension (2015 Grover Conference Series):

机译：肺动脉高压中的新型信号通路（2015年格罗弗会议系列）：

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The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis. Recently, the estrogen metabolite 16α-OHE1 (hydroxyestrone) was implicated in the regulation of miR29, a microRNA involved in modulating energy metabolism. In females, decreased miR96 enhances serotonin's effect by upregulating the 5-hydroxytryptamine 1B (5HT1B) receptor. Because PAH is characterized as a quasi-malignant disease, likely due to BMPR2 loss of function, altered signaling pathways that sustain this cancer-like phenotype are being explored. Extracellular signal–regulated kinases 1 and 2 and p38 mitogen-activated protein kinases (MAPKs) play a critical role in proliferation and cell motility, and dysregulated MAPK signaling is observed in various experimental models of PAH. Wnt signaling pathways preserve pulmonary vascular homeostasis, and dysregulation of this pathway could contribute to limited vascular regeneration in response to injury. In this review, we take a closer look at sex, sex hormones, and the interplay between sex hormones and microRNA regulation. We also focus on MAPK and Wnt signaling pathways in the emergence of a proproliferative, antiapoptotic endothelial phenotype, which then orchestrates an angioproliferative process of vascular remodeling, with the hope of developing novel therapies that could reverse the phenotype.
机译：增殖性内皮和平滑肌细胞表型，发炎和肺血管重塑是肺动脉高压（PAH）的突出特征。骨骼形态发生蛋白2型受体（BMPR2）的突变已被确定是PAH的最常见遗传原因，具有BMPR2突变的女性形成遗传性PAH的可能性是男性的2.5倍。在患有PAH的男性中也观察到更高水平的雌激素，这暗示了PAH发病机理中的性激素。最近，雌激素代谢物16α-OHE1（羟基雌酮）参与了miR29的调控，miR29是一种参与调节能量代谢的微小RNA。在女性中，降低的miR96通过上调5-羟色胺1B（5HT1B）受体来增强5-羟色胺的作用。由于PAH被表征为准恶性疾病，很可能是由于BMPR2功能丧失所致，因此正在探索改变维持这种癌症样表型的信号通路。细胞外信号调节激酶1、2和p38丝裂原活化蛋白激酶（MAPK）在增殖和细胞运动中起关键作用，并且在各种PAH实验模型中均观察到MAPK信号调节失调。 Wnt信号通路可保持肺血管稳态，而该通路的失调可能会导致有限的血管再生以应对损伤。在这篇综述中，我们仔细研究了性，性激素以及性激素与microRNA调控之间的相互作用。我们还着眼于促增殖，抗凋亡的内皮表型的出现中的MAPK和Wnt信号通路，然后协调血管重构的血管增殖过程，以期希望开发出可以逆转该表型的新疗法。

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