Characterisation of hypertrophic response and the effect of a GATA4-targeting compound on the phenotype of hypertrophic cardiomyopathy patient-derived hiPSC-cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer an informative platform to study pathomechanisms of HCM. Transcription factor GATA4-targeted compounds inhibit cardiomyocyte hypertrophy. hiPSC-CMs were differentiated from control line and HCM patient-derived hiPSCs (HCM hiPSC-CMs). hiPSC-CMs were subjected to mechanical stretching or exposed to endothelin-1 to induce hypertrophy. C-2021 was administered 1h before stimuli. The expression of hypertrophic markers and structural proteins was investigated with qPCR and HCA.
Control and HCM hiPSC-CMs displayed differential gene expression in response to cyclic mechanical stretching. The compound C-2021 inhibited stretch-induced NPPB expression after 72
h stretching. ET-1 increased proBNP expression to 2.8-fold in the control hiPSC-CMs but did not enhance proBNP expression in the HCM hiPSC-CMs.
Our results show that the HCM hiPSC-CMs differ from the control hiPSC-CMs in response to hypertrophic stimuli and in myosin heavy chain isoform expression. Additionally, C-2021 may have anti-hypertrophic effects in the HCM patient-derived hiPSC-CMs.