The small GTP-binding protein Rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear factor-kappa B.
The small guanine nucleotide-binding protein Rac1 has emerged as an important molecule involved in cardiac myocyte hypertrophy. Recently, we reported on apoptosis signal-regulating kinase (ASK) 1 and a transcriptional factor, nuclear factor-kappaB (NF-kappaB), as novel signaling intermediates in cardiac myocyte hypertrophy. The aim of the study presented here was to clarify the role of Rac1 in the ASK1-NF-kappaB signaling pathway. Infection of isolated neonatal cardiac myocytes with an adenovirus expressing a constitutively active form of Rac1 (RacV12) enhanced the expression of a kappaB-dependent reporter gene construct and induced the degradation of IkappaBalpha. Expression of a degradation-resistant mutant of IkappaBalpha inhibited the RacV12-induced hypertrophic responses, including increases in protein synthesis and atrial natriuretic factor production and the enhancement of sarcomeric organization. An immune complex kinase assay indicated that the expression of RacV12 activated ASK1. Expression of a dominant negative mutant of ASK1 eliminated the RacV12-induced NF-kappaB activation and the biochemical and morphological hypertrophic responses, whereas expression of a dominant negative form of Rac1 attenuated phenylephrine-induced activation of ASK1 and NF-kappaB and cardiac myocyte hypertrophy. These findings suggest that Rac1 induces cardiac myocyte hypertrophy mediated through ASK1 and NF-kappaB.
Higuchi
Yoshiharu
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-087, Japan.
Otsu
Kinya
K
Nishida
Kazuhiko
K
Hirotani
Shinichi
S
Nakayama
Hiroyuki
H
Yamaguchi
Osamu
O
Hikoso
Shungo
S
Kashiwase
Kazunori
K
Takeda
Toshihiro
T
Watanabe
Tetsuya
T
Mano
Toshiaki
T
Matsumura
Yasushi
Y
Ueno
Hikaru
H
Hori
Masatsugu
M
D000111:Acetylcysteine / Q000494:pharmacology; D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000975:Antioxidants; D016328:NF-kappa B; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D020830:rac1 GTP-Binding Protein; D000111:Acetylcysteine