Abstract
Atrial natriuretic factor (ANF) inhibits proliferation in non-myocardial cells and is thought to be anti-hypertrophic in cardiomyocytes. We investigated the possibility that the anti-hypertrophic actions of ANF involved the mitogen-activated protein kinase signal transduction cascade. Cultured neonatal rat ventricular myocytes treated for 48 h with the alpha(1)-adrenergic agonist phenylephrine (PE) had an 80% increase in cross-sectional area (CSA). ANF alone had no effect but inhibited PE-induced increases in CSA by approximately 50%. The mitogen-activated protein kinase/ERK kinase (MEK) inhibitor PD098059 minimally inhibited PE-induced increases in CSA, but it completely 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 and activation but failed to activate any of the Raf isoforms. ANF induced a rapid increase in ERK phosphorylation and in vitro kinase activity. PE also increased ERK activity, and the combined effect of ANF and PE appeared to be additive. ANF-induced ERK phosphorylation was eliminated by PD098059. ANF induced minimal phosphorylation of JNK or p38, indicating that its effect on ERK was specific. ANF-induced activation of ERK was mimicked by cGMP analogs, suggesting that ANF-induced ERK activation involves the guanylyl cyclase activity of the ANF receptor. These data suggest that there is an important linkage between cGMP signaling and the mitogen-activated protein kinase cascade and that selective ANF activation of ERK is required for the anti-hypertrophic action of ANF. Thus, ANF expression might function as the natural defense of the heart against maladaptive hypertrophy through its ability to activate ERK.
Highlights
Atrial natriuretic factor (ANF)1 is a peptide hormone that is normally expressed only in the cardiac atria and has a well characterized endocrine role in blood volume regulation [1]
ANF Inhibition of PE-induced Myocyte Hypertrophy Is ERKdependent (Fig. 1)—To confirm that ANF treatment inhibits PE-induced hypertrophy, we measured cross-sectional area (CSA) in primary cultures of neonatal rat ventricular myocytes (NRVMC)
To determine that ANF-induced activation of extracellular signal-regulated protein kinase (ERK) was necessary for its anti-hypertrophic actions, we assessed the ability of the mitogen-activated protein kinase/ERK kinase (MEK) antagonist PD098059 to inhibit the inhibitory effect of ANF on PE-induced increases in CSA
Summary
Atrial natriuretic factor (ANF)1 is a peptide hormone that is normally expressed only in the cardiac atria and has a well characterized endocrine role in blood volume regulation [1]. We have extended this observation by demonstrating that activation of the ERK cascade is required for the anti-hypertrophic action of ANF, and we have established that ANF-induced ERK activation through cGMP involves MEK but not Raf. Antibodies and Peptides—Antibodies to p44/42 MAPK (ERK1 and ERK2), p38 MAPK, SAPK/JNK, MEK1/2, and corresponding phosphospecific antibodies (when available) were purchased from New England Biolabs (Beverly, MA).
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