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/extracel lular 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 ac tivation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated wit h 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-49 0 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that th is cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pa thways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increas e in [H-3] 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. LI F-induced expression of c-fos, brain natriuretic peptide, and skeletal alph a-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly supp ressed by AG-490. These findings indicate that this pathway is critically i nvolved in protein synthesis, induction of c-fos, brain natriuretic peptide , and skeletal alpha-actin expression and is partially involved in myofilam ent reorganization and atrial natriuretic peptide induction in gp130-mediat ed cardiac hypertrophy.