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:info:doi/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	Yamaguchi, Osamu Yamaguchi, Osamu
	Watanabe, Tetsuya Watanabe, Tetsuya
	Nishida, Kazuhiko Nishida, Kazuhiko
	Kashiwase, Kazunori Kashiwase, Kazunori
	Higuchi, Yoshiharu Higuchi, Yoshiharu
	Takeda, Toshihiro Takeda, Toshihiro
	Hikoso, Shungo Hikoso, Shungo
	Hirotani, Shinichi Hirotani, Shinichi
	Asahi, Michio Asahi, Michio
	Taniike, Masayuki Taniike, Masayuki
	Nakai, Atsuko Nakai, Atsuko
	Tsujimoto, Ikuko Tsujimoto, Ikuko
	Matsumura, Yasushi Matsumura, Yasushi
	Miyazaki, Jun-ichi Miyazaki, Jun-ichi
	Chien, Kenneth R. Chien, Kenneth R.
	Matsuzawa, Atsushi Matsuzawa, Atsushi
	Sadamitsu, Chiharu Sadamitsu, Chiharu
	Ichijo, Hidenori Ichijo, Hidenori
	Baccarini, Manuela Baccarini, Manuela
	Hori, Masatsugu, Otsu, Kinya Hori, Masatsugu, 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.
公開者	American Society for Clinical Investigation
掲載誌名	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
ISSN	00219738
NCID	AA00695520
DOI	info:doi/10.1172/JCI20317
URL	http://hdl.handle.net/11094/23111
権利情報	Copyright © 2004 American Society for Clinical Investigation
言語	英語
カテゴリ	学術雑誌論文 Journal Article

著者版フラグ	publisher
NII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
DCTERMS.issued" scheme="DCTERMS.W3CDTF	2004-10
DC.identifier	info:doi/10.1172/JCI20317
DC.identifier" scheme="DCTERMS.URI	http://hdl.handle.net/11094/23111
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
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	info:doi/10.1172/JCI20317
citation_public_url	http://hdl.handle.net/11094/23111

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