title: Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice.
abstract: BACKGROUND
  Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na+/H+ exchanger NHE-1 to cardiac remodeling in GC-A-deficient (GC-A(-/-)) mice.
  
  
  RESULTS
  Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A(-/-) mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca2+ levels. Chronic treatment of GC-A(-/-) mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A(-/-) mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca2+/calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A(-/-) mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy.
  
  
  CONCLUSIONS
  On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca2+, and CaMKII as well as Akt activity.
authors.affiliation: Institute of Physiology, University of Würzburg, Würzburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilic
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.forename: León J
authors.initials: LJ
authors.lastname: De Windt
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Melanie
authors.initials: M
authors.lastname: Voss
authors.forename: Danuta
authors.initials: D
authors.lastname: Mitko
authors.forename: Melanie
authors.initials: M
authors.lastname: Zwiener
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Martin
authors.initials: M
authors.lastname: van Eickels
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D015342:DNA Probes; D004195:Disease Models, Animal; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006321:Heart / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D009200:Myocardial Contraction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
chemical_list: D000199:Actins; D015342:DNA Probes; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D012313:RNA; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D017461:Receptors, Atrial Natriuretic Factor