title: Enhanced hypertrophy in ob/ob mice due to an impairment in expression of atrial natriuretic peptide.
abstract: BACKGROUND
  We investigated the molecular mechanism(s) that play a role in leptin signaling during the development of left ventricular hypertrophy (LVH) due to pressure overload. To this end, ob/ob leptin deficient and C57BL/6J control mice were subjected transverse aortic constriction (TAC).
  
  
  METHODS
  Control sham C57BL/6J and ob/ob mice, along with C57BL/6J and ob/ob leptin deficient mice were subjected transverse aortic constriction (TAC) for 15 days and then evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy.
  
  
  RESULTS
  Evaluation by echocardiography revealed a significant increase in left ventricular mass (LVmass) and wall thickness in ob/ob mice subjected to transverse aortic constriction (TAC) as compared to C57BL/6J. Analysis of the expression of molecular markers of LVH, such as atrial natriuretic peptide (ANP), revealed a blunted increase in the level of ANP in ob/ob mice as compared to C57BL/6J mice. We observed that leptin plays a role in modulating the transcriptional activity of the promoter of the ANP gene. Leptin acts by regulating NFATc4, a member of the nuclear factor activated T cell (NFAT) family of transcription factors in cardiomyocytes. Our in vivo studies revealed that ob/ob mice subjected to TAC failed to activate the NFATc4 in the heart, however, intraperitoneal injection of leptin in ob/ob mice restored the NFATc4 DNA-binding activity and induced expression of the ANP gene.
  
  
  CONCLUSIONS
  This study establishes the role of leptin as an anti-hypertrophic agent during pressure overload hypertrophy, and suggests that a key molecular event is the leptin mediated activation of NFATc4 that regulates the transcriptional activation of the ANP gene promoter.
authors: Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. emascareno@downstate.edu
authors: Eduardo
authors: E
authors: Mascareno
authors: Daniel
authors: D
authors: Beckles
authors: Manya
authors: M
authors: Dhar-Mascareno
authors: M A Q
authors: MA
authors: Siddiqui
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003251:Constriction, Pathologic; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000502:physiology*; D005819:Genetic Markers; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020738:Leptin / Q000008:administration & dosage / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D032383:Myocytes, Cardiac / Q000187:drug effects; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051381:Rats; D013997:Time Factors; D020257:Ventricular Remodeling
chemical_list: D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D020738:Leptin; D050778:NFATC Transcription Factors; D009320:Atrial Natriuretic Factor