title: Differences in MEF2 and NFAT transcriptional pathways according to human heart failure aetiology.
abstract: BACKGROUND
  Ca(2+) handling machinery modulates the activation of cardiac transcription pathways involved in heart failure (HF). The present study investigated the effect of HF aetiology on Ca(+2) handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue.
  
  
  RESULTS
  A total of 83 hearts from ischemic (ICM, n = 43) and dilated (DCM, n = 31) patients undergoing heart transplantation and controls (CNT, n = 9) were analyzed by western blotting. Subcellular distribution was analyzed by fluorescence and electron microscopy. When we compared Ca(+2) handling proteins according to HF aetiology, ICM showed higher levels of calmodulin (24%, p<0.01), calcineurin (26%, p<0.01) and Ca(2+)/Calmodulin-dependent kinase II (CaMKIIδ(b) nuclear isoform 62%, p<0.001) than the CNT group. However, these proteins in DCM did not significantly increase. Furthermore, ICM showed a significant elevation in MEF2C (33%, p<0.01), and GATA4 (49%, p<0.05); also NFAT1 (66%, p<0.001) was increased, producing the resultant translocation of this transcriptional factor into the nuclei. These results were supported by fluorescence and electron microscopy analysis. Whereas, DCM only had a significant increase in GATA4 (52%, p<0.05). Correlations between NFAT1 and MEF2C in both groups (ICM r = 0.38 and DCM r = 0.59, p<0.05 and p<0.01, respectively) were found; only ICM showed a correlation between GATA4 and NFAT1 (r = 0.37, p<0.05).
  
  
  CONCLUSIONS
  This study shows an increase of Ca(2+) handling machinery synthesis and their cardiac transcription pathways in HF, being more markedly increased in ICM. Furthermore, there is a significant association between MEF2, NFAT1 and GATA4. These proteins could be therapeutic targets to improve myocardial function.
authors.affiliation: Cardiocirculatory Unit, Research Center, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cortés
authors.forename: Miguel
authors.initials: M
authors.lastname: Rivera
authors.forename: Esther
authors.initials: E
authors.lastname: Roselló-Lletí
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Dolz
authors.forename: Luis
authors.initials: L
authors.lastname: Almenar
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Azorín
authors.forename: Francisca
authors.initials: F
authors.lastname: Lago
authors.forename: José Ramón
authors.initials: JR
authors.lastname: González-Juanatey
authors.forename: Manuel
authors.initials: M
authors.lastname: Portolés
mesh_terms: D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D006570:Heterochromatin / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics* / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D014158:Transcription, Genetic; D014463:Ultrasonography
chemical_list: D002147:Calmodulin; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D006570:Heterochromatin; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D002118:Calcium