title: Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes.
abstract: Growth factors and cytokines trigger survival signaling in a wide variety of cell systems, including cardiac myocytes. Participation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway in survival signaling has already been described in some cell types, but its involvement in the survival of cardiac myocytes is as yet unknown. Recently, CT-1, an interleukin 6-related cytokine, was shown to have survival-promoting, anti-apoptotic effects on cultured cardiac myocytes. However, roles of PI3K-dependent pathways in this signaling have not been elucidated. In the present study, therefore, we examined the participation of the PI3K/Akt pathway in CT-1-induced, survival-promoting signaling in cultured ventricular myocytes. It was found that CT-1 phosphorylated and activated Akt, and the effect was blocked by the PI3K inhibitors LY294002 and wortmannin. CT-1 also phosphorylated the pro-apoptotic factor, BAD, and the BAD phosphorylation was inhibited by LY294002, suggesting that phosphorylation of BAD is one of the key events by which the PI3K/Akt pathway mediates CT-1-induced survival signaling. Further, CT-1 PI3K-dependently prolonged the survival of serum-starved ventricular myocytes by preventing apoptosis. In summary, our findings show that PI3K-dependent survival signals contribute to CT-1-mediated ventricular myocyte survival. In vivo, the death of ventricular myocytes leads to heart failure, and downregulation of survival signals and/or augmentation of pro-apoptotic signals are likely to be important components of disease processes. Thus, the extent to which CT-1 and the PI3K/Akt pathway mitigate such pathological processes, in vivo, is an important question for the future.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: I
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: M
authors.initials: M
authors.lastname: Harada
authors.forename: E
authors.initials: E
authors.lastname: Ogawa
authors.forename: I
authors.initials: I
authors.lastname: Hamanaka
authors.forename: N
authors.initials: N
authors.lastname: Kajiyama
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.forename: R
authors.initials: R
authors.lastname: Kawakami
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000494:pharmacology*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D051025:bcl-Associated Death Protein; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002352:Carrier Proteins; D004396:Coloring Agents; D016895:Culture Media, Serum-Free; D016207:Cytokines; D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D051025:bcl-Associated Death Protein; D048051:p38 Mitogen-Activated Protein Kinases; C494820:Bad protein, mouse; C494821:Bad protein, rat; C092073:cardiotrophin 1; C494920:Akt1 protein, rat; C022616:thiazolyl blue