Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

Yamaguchi, Osamu; Watanabe, Tetsuya; Nishida, Kazuhiko; Kashiwase, Kazunori; Higuchi, Yoshiharu; Takeda, Toshihiro; Hikoso, Shungo; Hirotani, Shinichi; Asahi, Michio; Taniike, Masayuki; Nakai, Atsuko; Tsujimoto, Ikuko; Matsumura, Yasushi; Miyazaki, Jun-ichi; Chien, Kenneth R.; Matsuzawa, Atsushi; Sadamitsu, Chiharu; Ichijo, Hidenori; Baccarini, Manuela; Hori, Masatsugu; Otsu, Kinya

doi:https://doi.org/10.1172/JCI20317

Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

Yamaguchi, Osamu; Watanabe, Tetsuya; Nishida, Kazuhiko et al.

Journal of Clinical Investigation, 2004, 114(7), 937-943

Number of Access:2,694（2025-11-19 04:10 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/23111

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Title	Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis
Creator	NRID 1000020174609 1000020174609 CreatorName Yamaguchi, Osamu
	NRID 1000040735122 1000040735122 CreatorName Watanabe, Tetsuya
	NRID 1000090362681 1000090362681 CreatorName Nishida, Kazuhiko
	CreatorName Kashiwase, Kazunori
	CreatorName Higuchi, Yoshiharu
	NRID 1000070506493 1000070506493 researchmap permalink ttakeda_research ttakeda_research Scopus Author ID 7403572788 7403572788 CreatorName Takeda, Toshihiro
	NRID 1000030423164 1000030423164 researchmap permalink hikoso_osakauniv hikoso_osakauniv Scopus Author ID 6507288830 6507288830 CreatorName Hikoso, Shungo
	NRID 1000020584220 1000020584220 CreatorName Hirotani, Shinichi
	NRID 1000010397614 1000010397614 CreatorName Asahi, Michio
	CreatorName Taniike, Masayuki
	CreatorName Nakai, Atsuko
	CreatorName Tsujimoto, Ikuko
	NRID 1000090252642 1000090252642 CreatorName Matsumura, Yasushi
	NRID 1000080229830 1000080229830 CreatorName Miyazaki, Jun-ichi
	CreatorName Chien, Kenneth R.
	NRID 1000080345256 1000080345256 CreatorName Matsuzawa, Atsushi
	NRID 1000050372420 1000050372420 CreatorName Sadamitsu, Chiharu
	NRID 1000000242206 1000000242206 CreatorName Ichijo, Hidenori
	CreatorName Baccarini, Manuela
	CreatorName Hori, Masatsugu
	CreatorName Otsu, Kinya
Abstract	The Raf/MEK/extracellular signal–regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal–regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK–independent mechanism.
Publisher	American Society for Clinical Investigation
Source Title	Journal of Clinical Investigation
Volume (Issue)	114(7)
Page	937-943
Date of Issued	2004-10
Language	English
Handle URL	https://hdl.handle.net/11094/23111
PISSN	00219738
NCID	AA00695520
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1172/JCI20317
Access Rights	open access
CopyRight	Copyright © 2004 American Society for Clinical Investigation
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of Clinical Investigation. 2004, 114(7), p. 937-943
DC.title	Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis
DC.creator	Yamaguchi, Osamu
	Watanabe, Tetsuya
	Nishida, Kazuhiko
	Kashiwase, Kazunori
	Higuchi, Yoshiharu
	Takeda, Toshihiro
	Hikoso, Shungo
	Hirotani, Shinichi
	Asahi, Michio
	Taniike, Masayuki
	Nakai, Atsuko
	Tsujimoto, Ikuko
	Matsumura, Yasushi
	Miyazaki, Jun-ichi
	Chien, Kenneth R.
	Matsuzawa, Atsushi
	Sadamitsu, Chiharu
	Ichijo, Hidenori
	Baccarini, Manuela
	Hori, Masatsugu
	Otsu, Kinya
DC.publisher	American Society for Clinical Investigation
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2004-10
DC.identifier	https://doi.org/10.1172/JCI20317
DCTERMS.abstract	The Raf/MEK/extracellular signal–regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal–regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK–independent mechanism.
DC.rights	Copyright © 2004 American Society for Clinical Investigation
DC.format	23111
citation_title	Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis
citation_author	Yamaguchi, Osamu
	Watanabe, Tetsuya
	Nishida, Kazuhiko
	Kashiwase, Kazunori
	Higuchi, Yoshiharu
	Takeda, Toshihiro
	Hikoso, Shungo
	Hirotani, Shinichi
	Asahi, Michio
	Taniike, Masayuki
	Nakai, Atsuko
	Tsujimoto, Ikuko
	Matsumura, Yasushi
	Miyazaki, Jun-ichi
	Chien, Kenneth R.
	Matsuzawa, Atsushi
	Sadamitsu, Chiharu
	Ichijo, Hidenori
	Baccarini, Manuela
	Hori, Masatsugu
	Otsu, Kinya
citation_publisher	American Society for Clinical Investigation
citation_language	English
citation_date	2004-10
citation_journal_title	Journal of Clinical Investigation
citation_volume	114
citation_issue	7
citation_firstpage	937
citation_lastpage	943
citation_doi	https://doi.org/10.1172/JCI20317
citation_public_url	https://hdl.handle.net/11094/23111

Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

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