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

Masanobu Morita; Osamu Ohneda; Toshiharu Yamashita; Satoru Takahashi; Norio Suzuki; Osamu Nakajima; Shimako Kawauchi; Masatsugu Ema; Shigeki Shibahara; Tetsuo Udono; Makoto Tamai; Kazuhiro Sogawa; Masayuki Yamamoto; Yoshiaki Fujii-Kuriyama

doi:10.1093/emboj/cdg117

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

Masanobu Morita, Osamu Ohneda, Toshiharu Yamashita, Satoru Takahashi, Norio Suzuki, Osamu Nakajima, Shimako Kawauchi, Masatsugu Ema, Shigeki Shibahara, Tetsuo Udono, Makoto Tamai, Kazuhiro Sogawa, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journal › Article › peer-review

160 Citations (Scopus)

Abstract

An HLF (HIF-1α-like factor)/HIF-2α-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/kdmice 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/dmice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLF^kd/kdmice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLF^kd/kdmice. 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/kdmouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

Original language	English
Pages (from-to)	1134-1146
Number of pages	13
Journal	EMBO Journal
Volume	22
Issue number	5
DOIs	https://doi.org/10.1093/emboj/cdg117
Publication status	Published - 2003 Mar 3
Externally published	Yes

Keywords

Erythropoietin
HLF
Neovascularization
Retinopathy
VEGF

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.1093/emboj/cdg117

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title = "HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin",

abstract = "An HLF (HIF-1α-like factor)/HIF-2α-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 (HLFkd/kd)mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLFkd/kdmice 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 HLFkd/dmice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLFkd/kdmice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLFkd/kdmice. 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 HLFkd/kdmouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.",

keywords = "Erythropoietin, HLF, Neovascularization, Retinopathy, VEGF",

author = "Masanobu Morita and Osamu Ohneda and Toshiharu Yamashita and Satoru Takahashi and Norio Suzuki and Osamu Nakajima and Shimako Kawauchi and Masatsugu Ema and Shigeki Shibahara and Tetsuo Udono and Makoto Tamai and Kazuhiro Sogawa and Masayuki Yamamoto and Yoshiaki Fujii-Kuriyama",

year = "2003",

month = mar,

day = "3",

doi = "10.1093/emboj/cdg117",

language = "English",

volume = "22",

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journal = "EMBO Journal",

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T1 - HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

AU - Morita, Masanobu

AU - Ohneda, Osamu

AU - Yamashita, Toshiharu

AU - Takahashi, Satoru

AU - Suzuki, Norio

AU - Nakajima, Osamu

AU - Kawauchi, Shimako

AU - Ema, Masatsugu

AU - Shibahara, Shigeki

AU - Udono, Tetsuo

AU - Tamai, Makoto

AU - Sogawa, Kazuhiro

AU - Yamamoto, Masayuki

AU - Fujii-Kuriyama, Yoshiaki

PY - 2003/3/3

Y1 - 2003/3/3

N2 - An HLF (HIF-1α-like factor)/HIF-2α-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 (HLFkd/kd)mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLFkd/kdmice 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 HLFkd/dmice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLFkd/kdmice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLFkd/kdmice. 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 HLFkd/kdmouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

AB - An HLF (HIF-1α-like factor)/HIF-2α-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 (HLFkd/kd)mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLFkd/kdmice 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 HLFkd/dmice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLFkd/kdmice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLFkd/kdmice. 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 HLFkd/kdmouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

KW - Erythropoietin

KW - HLF

KW - Neovascularization

KW - Retinopathy

KW - VEGF

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U2 - 10.1093/emboj/cdg117

DO - 10.1093/emboj/cdg117

M3 - Article

C2 - 12606578

AN - SCOPUS:0037416792

SN - 0261-4189

VL - 22

SP - 1134

EP - 1146

JO - EMBO Journal

JF - EMBO Journal

IS - 5

ER -

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

Abstract

Keywords

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