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Molecular and Cellular Biology, February 2008, p. 1285-1297, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01332-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS{triangledown}

Toshiharu Yamashita,1,{dagger} Osamu Ohneda,1,{dagger}* Masumi Nagano,1 Motoyuki Iemitsu,2 Yuichi Makino,5 Hirotoshi Tanaka,5 Takashi Miyauchi,3 Katsutoshi Goto,4 Kinuko Ohneda,6 Yoshiaki Fujii-Kuriyama,7 Lorenz Poellinger,8 and Masayuki Yamamoto9*

Department of Regenerative Medicine,1 Department of Molecular Pharmacology, Institute of Basic Medical Sciences,4 Institute of Health and Sport Sciences,2 Cardiovascular Division of Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan,3 Division of Clinical Immunology, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,5 Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan,6 Center for TARA and JST-SORST project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan,7 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden,8 Center for TARA and JST-ERATO Environmental Response Project, 1-1-1 Tennoudai, Tsukuba 305-8577, and Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan9

Received 25 July 2007/ Returned for modification 8 September 2007/ Accepted 20 November 2007

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-3{alpha} gene by alternative splicing, replacing the first exon of HIF-3{alpha} with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3{alpha}. NEPAS suppressed reporter gene expression driven by HIF-1{alpha} and HIF-2{alpha}. By generating mice with a targeted disruption of the NEPAS/HIF-3{alpha} locus, we found that homozygous mutant mice (NEPAS/HIF-3{alpha}–/–) 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-3{alpha}-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1{alpha} and HIF-2{alpha} are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.

* Corresponding author. Mailing address for Osamu Ohneda: Department of Regenerative Medicine, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan. Phone and fax: 81-29-853-2938. E-mail: oohneda{at}md.tsukuba.ac.jp. Mailing address for Masayuki Yamamoto: Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8084. Fax: 81-22-717-8090. E-mail: masi{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 10 December 2007.

{dagger} T. Yamashita and O. Ohneda contributed equally to this work.

Molecular and Cellular Biology, February 2008, p. 1285-1297, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01332-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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