Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes

Atrial natriuretic factor (ANF) inhibits proliferation in non-myocardial ce lls and is thought to be anti-hypertrophic in cardiomyocytes. We investigat ed the possibility that the anti-hypertrophic actions of ANF involved the m itogen-activated protein kinase signal transduction cascade. Cultured neona tal rat ventricular myocytes treated for 48 h with the alpha(1)-adrenergic agonist phenylephrine (PE) had an 80% increase in cross-sectional area (CSA ). ANP alone had no effect but inhibited PE-induced increases in CSA by app roximately 50%. The mitogen-activated protein kinase/ERK kinase (MER) inhib itor PD098059 minimally inhibited PE-induced increases in CSA, but it compl etely abolished ANF-induced inhibition of PE-induced increases, ANF-induced extracellular signal-regulated protein kinase (ERK) nuclear translocation was also eliminated by PD098059, ANF treatment caused MEK phosphorylation a nd activation but failed to activate any of the Raf isoforms, ANF induced a rapid increase in ERK phosphorylation and in vitro kinase activity. PE als o increased ERK activity, and the combined effect of ANF and PE appeared to be additive. ANF-induced ERK phosphorylation was eliminated by PD098059, A NF induced minimal phosphorylation of JNK or p38, indicating that its effec t on ERK was specific. ANF-induced activation of ERK was mimicked by cGMP a nalogs, suggesting that ANF-induced ERK activation involves the guanylyl cy clase activity of the ANF receptor. These data suggest that there is an imp ortant linkage between cGMP signaling and the mitogen-activated protein kin ase cascade and that selective ANF activation of ERK is required for the an ti-hypertrophic action of ANF. Thus, ANF expression might function as the n atural defense of the heart against maladaptive hypertrophy through its abi lity to activate ERK.