Overt expression of AP-1 reduces alpha myosin heavy chain expression and contributes to heart failure from chronic volume overload

Abstract

Reduced expression of α-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 α-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 α-MHC repression. The present study was performed to identify volume overload responsive transcription factors involved in α-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 β-MHC, and decreased expression of α-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 α-MHC mRNA by 60%. Transient transfection assays mapped PMA responsive sequence to − 582 to − 588 bp of α-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 α-MHC promoter activity. Over-expression of c-fos and c-jun in cardiomyocytes inhibited α-MHC promoter activity in a concentration dependent manner. Data suggest a repressive role of AP-1 in α-MHC expression and its possible involvement in the transition from compensatory hypertrophy to heart failure in chronic volume overload.