title: Overt expression of AP-1 reduces alpha myosin heavy chain expression and contributes to heart failure from chronic volume overload.
abstract: Reduced expression of alpha-MHC plays a significant role in cardiac contractile dysfunction from hemodynamic overload. Previously, Pur proteins and YY1 have been shown to play a role in alpha-MHC repression during heart failure induced by pressure overload and by spontaneous hypertension, respectively. This was not observed in volume-overload-induced heart failure, suggesting additional regulatory mechanisms for alpha-MHC repression. The present study was performed to identify volume overload responsive transcription factors involved in alpha-MHC gene regulation. DNA binding activity of several transcription factors was evaluated in a functionally characterized rat model of heart failure induced by aorto-caval shunt. After 10 weeks of shunt, severe LV dilatation and reduced LV function were accompanied by increased expression of ANF and beta-MHC, and decreased expression of alpha-MHC. This was associated with dramatic (10-fold) activation of AP-1 together with increased expression of c-fos and c-jun. AP-1 activation was not observed following 4 weeks of shunt when cardiac function was preserved. In cultured cardiomyocytes, induction of AP-1 by PMA attenuated alpha-MHC mRNA by 60%. Transient transfection assays mapped PMA responsive sequence to -582 to -588 bp of alpha-MHC promoter. Deletion or mutation of these nucleotides had minimal effect on basal promoter activity but played a dominant role in PMA-mediated repression of alpha-MHC promoter activity. Over-expression of c-fos and c-jun in cardiomyocytes inhibited alpha-MHC promoter activity in a concentration dependent manner. Data suggest a repressive role of AP-1 in alpha-MHC expression and its possible involvement in the transition from compensatory hypertrophy to heart failure in chronic volume overload.
authors.affiliation: The Heart Institute for Children, Advocate Hope Children's Hospital, Oak Lawn, IL, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Freire
authors.forename: Catherina
authors.initials: C
authors.lastname: Ocampo
authors.forename: Nadim
authors.initials: N
authors.lastname: Ilbawi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffin
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001835:Body Weight; D002306:Cardiac Volume / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D016762:Genes, fos; D016758:Genes, jun; D006333:Heart Failure / Q000235:genetics*; D008297:Male; D009206:Myocardium / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D016277:Ventricular Function, Left / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D024723:Ventricular Myosins