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

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論文情報

タイトル	Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis
著者	NRID 1000020174609 1000020174609 著者名 Yamaguchi, Osamu
	NRID 1000040735122 1000040735122 著者名 Watanabe, Tetsuya
	NRID 1000090362681 1000090362681 著者名 Nishida, Kazuhiko
	著者名 Kashiwase, Kazunori
	著者名 Higuchi, Yoshiharu
	NRID 1000070506493 1000070506493 著者名 Takeda, Toshihiro
	NRID 1000030423164 1000030423164 著者名 Hikoso, Shungo
	NRID 1000020584220 1000020584220 著者名 Hirotani, Shinichi
	NRID 1000010397614 1000010397614 著者名 Asahi, Michio
	著者名 Taniike, Masayuki
	著者名 Nakai, Atsuko
	著者名 Tsujimoto, Ikuko
	NRID 1000090252642 1000090252642 著者名 Matsumura, Yasushi
	NRID 1000080229830 1000080229830 著者名 Miyazaki, Jun-ichi
	著者名 Chien, Kenneth R.
	NRID 1000080345256 1000080345256 著者名 Matsuzawa, Atsushi
	NRID 1000050372420 1000050372420 著者名 Sadamitsu, Chiharu
	NRID 1000000242206 1000000242206 著者名 Ichijo, Hidenori
	著者名 Baccarini, Manuela
	著者名 Hori, Masatsugu
	著者名 Otsu, Kinya
抄録	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.
出版者	American Society for Clinical Investigation
収録物名	Journal of Clinical Investigation
巻	114
号	7
開始ページ	937
終了ページ	943
刊行年月	2004-10
言語	英語
ハンドルURL	https://hdl.handle.net/11094/23111
ISSN	00219738
NCID	AA00695520
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1172/JCI20317
アクセス権	open access
権利情報	Copyright © 2004 American Society for Clinical Investigation
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Journal of Clinical Investigation.114(7) p.937-p.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	英語
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	application/pdf
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	英語
citation_date	2004-10
citation_journal_title	Journal of Clinical Investigation
citation_volume	114
citation_issue	7
citation_firstpage	937
citation_lastpage	943
citation_issn	00219738
citation_doi	https://doi.org/10.1172/JCI20317
citation_public_url	https://hdl.handle.net/11094/23111

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