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首页> 外文期刊>Molecular and Cellular Biology >The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway
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The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway

机译：阿米洛利衍生物苯丙胺通过激活NFAT和骨形态发生蛋白信号通路来减轻肺血管重构。

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Pulmonary artery hypertension (PAH) is characterized by elevated pulmonary artery resistance and increased medial thickness due to deregulation of vascular remodeling. Inactivating mutations of the BMPRII gene, which encodes a receptor for bone morphogenetic proteins (BMPs), are identified in ～60% of familial PAH (FPAH) and ～30% of idiopathic PAH (IPAH) patients. It has been hypothesized that constitutive reduction in BMP signal by BMPRII mutations may cause abnormal vascular remodeling by promoting dedifferentiation of vascular smooth muscle cells (vSMCs). Here, we demonstrate that infusion of the amiloride analog phenamil during chronic-hypoxia treatment in rat attenuates development of PAH and vascular remodeling. Phenamil induces Tribbles homolog 3 (Trb3), a positive modulator of the BMP pathway that acts by stabilizing the Smad family signal transducers. Through induction of Trb3, phenamil promotes the differentiated, contractile vSMC phenotype characterized by elevated expression of contractile genes and reduced cell growth and migration. Phenamil activates the Trb3 gene transcription via activation of the calcium-calcineurin-nuclear factor of activated T cell (NFAT) pathway. These results indicate that constitutive elevation of Trb3 by phenamil is a potential therapy for IPAH and FPAH.
机译：肺动脉高压（PAH）的特征是由于血管重塑失调，肺动脉阻力增加，内侧厚度增加。在大约60％的家族性PAH（FPAH）和大约30％的特发性PAH（IPAH）患者中发现了编码骨形态发生蛋白（BMP）受体的 BMPRII 基因的失活突变。据推测，由BMPRII突变引起的BMP信号组成型减少可能会通过促进血管平滑肌细胞（vSMCs）的去分化而引起异常的血管重塑。在这里，我们证明了在大鼠慢性低氧治疗过程中输注阿米洛利类似物苯那非可减轻PAH的发展和血管重塑。苯丙胺可诱导Tribbles同源物3（Trb3），它是BMP途径的正调节剂，可通过稳定Smad家族信号转导子发挥作用。通过Trb3的诱导，苯那米尔可促进分化的，收缩的vSMC表型，其特征是收缩基因的表达升高，细胞生长和迁移减少。苯丙胺通过激活的T细胞（NFAT）途径的钙-钙调神经磷酸酶-核因子的激活来激活Trb3基因转录。这些结果表明，苯那米尔使Trb3组成型升高是IPAH和FPAH的潜在疗法。

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