title: Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes.
abstract: gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Masaki
authors.initials: M
authors.lastname: Harada
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Rika
authors.initials: R
authors.lastname: Kawakami
authors.forename: Michio
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D005419:Flavonoids; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; C092073:cardiotrophin 1; D048054:Mitogen-Activated Protein Kinase 7; D048369:MAP Kinase Kinase 1; D048671:MAP Kinase Kinase 5; C482565:Map2k5 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one