Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy.
We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90(RSK) cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated with leukemia inhibitory factor (LIF). LIF sequentially activated Raf-1, MEK1/2, ERK1/2, and p90(RSK). We used PD-98059 (a specific MEK inhibitor), AG-490 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that this cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pathways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increase in [(3)H]phenylalanine uptake by 54.7, 21.5, and 25.6%, respectively, and inhibited the increase in cell area by 61.2, 42.8, and 39.2%, respectively. Reorganization of myofilaments was predominantly suppressed by AG-490. LIF-induced expression of c-fos, brain natriuretic peptide, and skeletal alpha-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly suppressed by AG-490. These findings indicate that this pathway is critically involved in protein synthesis, induction of c-fos, brain natriuretic peptide, and skeletal alpha-actin expression and is partially involved in myofilament reorganization and atrial natriuretic peptide induction in gp130-mediated cardiac hypertrophy.
Kodama
H
H
Cardiopulmonary Division, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Fukuda
K
K
Pan
J
J
Sano
M
M
Takahashi
T
T
Kato
T
T
Makino
S
S
Manabe
T
T
Murata
M
M
Ogawa
S
S
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology* / Q000209:etiology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D005419:Flavonoids / Q000494:pharmacology; D005819:Genetic Markers; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010649:Phenylalanine / Q000493:pharmacokinetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D015703:Antigens, CD; D005419:Flavonoids; D005819:Genetic Markers; D006131:Growth Inhibitors; C494201:Il6st protein, rat; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D050822:Cytokine Receptor gp130; D010649:Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin