The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension
The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension
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DOI：
10.1126/scisignal.aay4430
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发表时间：
2019-11-12
影响因子：
7.3
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Morikawa, Masato;Mitani, Yoshihide;Miyazono, Kohei
内皮细胞（EC）中骨形态发生蛋白（BMP）信号转导失调与肺动脉高压（PAH）等血管疾病有关。在这里，我们发现转录因子ATOH 8是SMAD 1/5的直接靶点，并且以依赖于BMP但独立于Notch的方式诱导，Notch是EC中的另一个关键信号通路。在斑马鱼和小鼠中，Atoh 8的失活不会导致动静脉畸形样表型，这可能是由于Notch信号失调而引起的。相反，Atoh 8缺陷小鼠表现出类似PAH的表型，包括肺动脉压升高和右心室肥大。此外，PAH患者肺中ATOH 8表达降低。我们发现，在细胞中，ATOH 8与低氧诱导因子2 α（HIF-2 α）相互作用，并降低其丰度，导致低氧诱导HIF-2 α靶基因减少。总之，这些研究结果表明，BMP受体II型/ALK-1/SMAD/ATOH 8轴可以减弱肺循环中EC的缺氧反应，并可能有助于预防PAH的发展。
Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation-like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, ATOH8 expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2 alpha (HIF-2 alpha) and decreased its abundance, leading to reduced induction of HIF-2 alpha target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.