Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro

Although MAP (mitogen-activated protein) kinases are implicated in cell pro liferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellul ar signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared wit h phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenyl ephrine caused stronger and more sustained activation of JNK and p3X than A ng II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK), inhibited An g II-induced, but not phenylephrine-induced, expression of atrial natriuret ic factor (ANF) at both the mRNA and polypeptide levels. 3B203580, a specif ic inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promot er, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Ph enylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negati ve MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-reg ulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal a lpha-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist -specific and phenotype-specific response in cardiac hypertrophy.