In this study, we showed that genetic deletion of EC-Foxp1 limited the simvastatin-mediated protective effect on pathological cardiac fibrosis and hypertrophy, demonstrating that the EC-Klf2-Foxp1-TGFβ1 transcription network is necessary for the protective effects of simvastatin against TAC pressure overload-induced cardiac remodeling in vivo. Here, KLF2 is linked to persistent truncus arteriosus.