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PMID: 12606578 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin.

The EMBO journal ·Vol. 22 ·No. 5 ·2003-03-03 ·Pages 1134-46

Morita M, Ohneda O, Yamashita T, Takahashi S, Suzuki N, Nakajima O, Kawauchi S, Ema M, Shibahara S, Udono T, Tomita K, Tamai M, Sogawa K, Yamamoto M, Fujii-Kuriyama Y

Abstract

An HLF (HIF-1alpha-like factor)/HIF-2alpha-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF-knockdown (HLF(kd/kd)) mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLF(kd/kd) mice expressing 80-20% reduction, depending on the tissue, in wild-type HLF mRNA were fertile and apparently normal. Hyperoxia-normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild-type mice, but not in HLF(kd/kd) mice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLF(kd/kd) mice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLF(kd/kd) mice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was significantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLF(kd/kd) mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

MeSH Terms
Animals Antibodies/metabolism Basic Helix-Loop-Helix Transcription Factors Disease Models, Animal Electroretinography Erythropoietin/metabolism Female Gene Expression Regulation Gene Targeting Genetic Vectors Helix-Loop-Helix Motifs Humans Hyperoxia/metabolism Hypoxia-Inducible Factor 1, alpha Subunit Immunohistochemistry In Situ Nick-End Labeling Infant, Newborn Integrases/genetics,metabolism Mice Mice, Knockout RNA, Messenger/metabolism Retina/cytology,metabolism,pathology Retinal Neovascularization Retinopathy of Prematurity/metabolism Tissue Distribution Trans-Activators/genetics,metabolism Transcription Factors/genetics,metabolism Vimentin/metabolism Viral Proteins/genetics,metabolism
Chemicals
Antibodies Basic Helix-Loop-Helix Transcription Factors HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit RNA, Messenger Trans-Activators Transcription Factors Vimentin Viral Proteins Erythropoietin endothelial PAS domain-containing protein 1 Cre recombinase Integrases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Morita Masanobu
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Ohneda Osamu
Yamashita Toshiharu
Takahashi Satoru
Suzuki Norio
Nakajima Osamu
Kawauchi Shimako
Ema Masatsugu
Shibahara Shigeki
Udono Tetsuo
Tomita Koji
Tamai Makoto
Sogawa Kazuhiro
Yamamoto Masayuki
Fujii-Kuriyama Yoshiaki
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg117
Published
2003-03-03
Pages
1134-46
Language
English
Region
England
NLM ID
8208664
PMCID
PMC150350
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdg117 PMC Full Text View journal details
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