Disruption of a GATA4/Ankrd1 Signaling Axis in Cardiomyocytes Leads to Sarcomere Disarray: Implications for Anthracycline Cardiomyopathy
Figure 12
Cardiac sarcomere structure is maintained by a balance between sarcomere protein synthesis and degradation.
We postulate that GATA4 regulates CARP expression and both act to induce sarcomere gene transcription. CARP expression is subject to a negative feedback regulatory mechanism. GATA4 siRNA and CARP siRNA both inhibit CARP signaling and sarcomere gene expression, resulting in an imbalance in protein turnover and eventual sarcomere disruption. Doxorubicin (actions marked by red x in figure) exacerbates sarcomere disruption by downregulation of GATA4 and CARP, degrading key sarcomeric proteins (e.g. titin), and inhibiting new sarcomere protein synthesis via transcriptional/translational impairment.