title: MEF2 transcriptional activity maintains mitochondrial adaptation in cardiac pressure overload.
abstract: OBJECTIVE
  The transcription factor MEF2 is a downstream target for several hypertrophic signalling pathways in the heart, suggesting that MEF2 may act as a valuable therapeutic target in the treatment of heart failure.
  
  
  RESULTS
  In this study, we investigated the potential benefits of overall MEF2 inhibition in a mouse model of chronic pressure overloading, by subjecting transgenic mice expressing a dominant negative form of MEF2 (DN-MEF2 Tg) in the heart, to transverse aortic constriction (TAC). Histological analysis revealed no major differences in cardiac remodelling between DN-MEF2 Tg and control mice after TAC. Surprisingly, echocardiographic analysis revealed that DN-MEF2 Tg mice had a decrease in cardiac function compared with control animals. Analysis of the mitochondrial respiratory chain showed that DN-MEF2 Tg mice displayed lower expression of NADH dehydrogenase subunit 6 (ND6), part of mitochondrial Complex I. The reduced expression of ND6 in DN-MEF2 Tg mice after pressure overload correlated with an increase in cell death secondary to overproduction of reactive oxygen species (ROS).
  
  
  CONCLUSIONS
  Our data suggest that MEF2 transcriptional activity is required for mitochondrial function and its inhibition predisposes the heart to impaired mitochondrial function, overproduction of ROS, enhanced cell death, and cardiac dysfunction, following pressure overload.
authors.affiliation: Department of Cardiology, Faculty of Health, Medicine and Life Sciences, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Hamid
authors.initials: H
authors.lastname: el Azzouzi
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Wim
authors.initials: W
authors.lastname: Sluiter
authors.forename: Martin W
authors.initials: MW
authors.lastname: Bergmann
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D015870:Gene Expression; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000235:genetics; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D009245:NADH Dehydrogenase / Q000172:deficiency; D014158:Transcription, Genetic; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009245:NADH Dehydrogenase; C508029:NADH dehydrogenase subunit 6, mouse; C045073:Cre recombinase; D019426:Integrases; D003849:Deoxyguanosine