Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes.
Early heart failure is characterized by elevated plasma atrial natriuretic peptide (ANP) levels, but little is known about the direct effects of ANP on cardiac myocytes. In neonatal rat cardiac myocytes, ANP induced apoptosis in a dose-dependent and cell type-specific manner. Maximum effects occurred at 1 microM ANP, with a 4-5-fold increase in apoptotic cells, reaching a maximum apoptotic index of 19%. In contrast, the maximum apoptotic index of ANP-treated non-myocytes was 1.1 +/- 0.2%, equivalent to control cultures. ANP treatment also sharply reduced levels of Mcl-1 mRNA, a Bcl-2 homologue, coincident with the increase in the incidence of apoptosis. ANP induction of apoptosis was receptor-dependent and mediated by cyclic GMP: the effect was mimicked by 8-bromo-cGMP, a membrane-permeable analog, and by sodium nitroprusside, an activator of soluble guanylyl cyclase, and was potentiated by a cGMP-specific phosphodiesterase inhibitor, zaprinast. Interestingly, norepinephrine, a myocyte growth factor, inhibited ANP-induced apoptosis via activation of the beta-adrenergic receptor and elevation of cyclic AMP. These results show that ANP is a specific effector of cardiac myocyte apoptosis in culture via receptor-mediated elevation of cGMP. Furthermore, at least in this model, ANP and norepinephrine may have opposing roles in the modulation of cardiac myocyte growth and survival.
Wu
C F
CF
Falk Cardiovascular Research Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Bishopric
N H
NH
Pratt
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RE
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D053938:DNA Fragmentation; D003893:Desmin / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009206:Myocardium / Q000166:cytology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D003893:Desmin; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010726:Phosphodiesterase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011688:Purinones; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009320:Atrial Natriuretic Factor; C041226:Terazosin; D011433:Propranolol; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D017461:Receptors, Atrial Natriuretic Factor; C011145:zaprinast; D006152:Cyclic GMP; D009638:Norepinephrine; D011224:Prazosin