Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS

Toshiharu Yamashita, Osamu Ohneda, Masumi Nagano, Motoyuki Iemitsu, Yuichi Makino, Hirotoshi Tanaka, Takashi Miyauchi, Katsutoshi Goto, Kinuko Ohneda, Yoshiaki Fujii-Kuriyama, Lorenz Poellinger, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)

Abstract

Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3α gene by alternative splicing, replacing the first exon of HIF-3α with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3α. NEPAS suppressed reporter gene expression driven by HIF-1α and HIF-2α. By generating mice with a targeted disruption of the NEPAS/HIF-3α locus, we found that homozygous mutant mice (NEPAS/HIF-3α-/-) were viable but displayed enlargement of the right ventricle and impaired lung remodeling. The expression of endothelin 1 and platelet-derived growth factor β was increased in the lung endothelial cells of NEPAS/HIF-3α-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1α and HIF-2α are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.

Original languageEnglish
Pages (from-to)1285-1297
Number of pages13
JournalMolecular and cellular biology
Volume28
Issue number4
DOIs
Publication statusPublished - 2008 Feb
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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