PUBLICATION

The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension

Authors
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, C.H., Miyazono, K.
ID
ZDB-PUB-191114-21
Date
2019
Source
Science signaling   12(607): (Journal)
Registered Authors
Bessho, Yasumasa, Holmborn, Katarina, Ledin, Johan
Keywords
none
MeSH Terms
  • 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
PubMed
31719172 Full text @ 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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping