PI 3-kinase-Akt-p70 S6 kinase in hypertrophic responses to leukemia inhibitory factor in cardiac myocytes.
Leukemia inhibitory factor (LIF) is a member of interleukin-6 related cytokines, which induces cardiac hypertrophy through glycoprotein (gp) 130. In this study, the role of phosphatidylinositol (PI) 3-kinase, Akt/protein kinase B (Akt/PKB), and p70 S6 kinase activation in LIF-induced hypertrophic responses such as stimulation of protein synthesis, atrial natriuretic peptide (ANP) gene expression, and reorganization of actin filaments into sarcomeric units was investigated in cultured cardiac myocytes. Treatment of cells with LIF resulted in sequential activation of PI 3-kinase, Akt/PKB, and p70 S6 kinase. Using inhibitors for PI 3-kinase and p70 S6 kinase activation, and adenovirus-mediated expression of dominant negative mutants of PI 3-kinase and Akt/PKB, we showed that PI 3-kinase activation was essential for stimulation of protein synthesis, ANP gene expression, and sarcomeric reorganization induced by LIF, while Akt/PKB activation was indispensable for ANP expression and stimulation of protein synthesis, but not for sarcomeric reorganization. Activation of p70 S6 kinase was necessary for stimulation of protein synthesis, but not for ANP gene expression or sarcomeric reorganization. These results indicated the essential role of PI 3-kinase-Akt/PKB-p70 S6 kinase pathway in the LIF-induced hypertrophic responses in cardiac myocytes.
Hiraoka
Eiji
E
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine.
Kawashima
Seinosuke
S
Takahashi
Tomosaburo
T
Rikitake
Yoshiyuki
Y
Hirase
Tetsuaki
T
Yokoyama
Mitsuhiro
M
D015152:Blotting, Northern; D009202:Cardiomyopathies / Q000201:enzymology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D006984:Hypertrophy / Q000201:enzymology* / Q000503:physiopathology; D007231:Infant, Newborn; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012680:Sensitivity and Specificity
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa