RRC ID 58262
著者 Morikawa M, Mitani Y, Holmborn K, Kato T, Koinuma D, Maruyama J, Vasilaki E, Sawada H, Kobayashi M, Ozawa T, Morishita Y, Bessho Y, Maeda S, Ledin J, Aburatani H, Kageyama R, Maruyama K, Heldin CH, Miyazono K.
タイトル The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension.
ジャーナル Sci Signal
Abstract 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 2α (HIF-2α) and decreased its abundance, leading to reduced induction of HIF-2α 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.
巻・号 12(607)
公開日 2019-11-12
DOI 10.1126/scisignal.aay4430
PII 12/607/eaay4430
PMID 31719172
PMC PMC6908447
MeSH Activin Receptors, Type II / genetics Activin Receptors, Type II / metabolism* Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* HEK293 Cells Humans Hypertension, Pulmonary / genetics Hypertension, Pulmonary / metabolism* Hypertension, Pulmonary / pathology Hypertension, Pulmonary / prevention & control* Hypoxia / genetics Hypoxia / metabolism* Hypoxia / pathology Mice Mice, Knockout Signal Transduction* Smad Proteins / genetics Smad Proteins / metabolism* Zebrafish
IF 6.467
引用数 0
リソース情報
遺伝子材料 CSII-EF-RfA (RDB04387) CS-CDF-CG-PRE (RDB04379)