Regulation of ICa,L and force by PDEs in human-induced pluripotent stem cell-derived cardiomyocytes

Abstract

Background and purpose: Phosphodiesterases (PDEs) are important regulators of β-adrenoceptor signalling in the heart. While PDE4 is the most important isoform that regulates I_Ca,L and force in rodent cardiomyocytes, the dominant isoform in adult human cardiomyocytes is PDE3.

Experimental approach: Given the potential of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for biomedical research, this study characterized the contribution of PDE3 and PDE4 isoforms to the regulation of I_Ca,L and force in hiPSC-CMs in an engineered heart tissue (EHT) model.

Key results: There was a lower abundance of mRNA for PDE3A and 4A in hiPSC-CM EHT than in non-failing human heart samples. Selective inhibition of PDE3 and 4 with cilostamide and rolipram, respectively, showed that, in hiPSC-CM, PDE4 was the predominant isoform for the regulation of I_Ca,L (cilostamide: +1.44-fold; rolipram: +1.77-fold)_. Furthermore, in contrast to cilostamide, rolipram decreased the EC₅₀ of isoprenaline about 15-fold.

Conclusion and implications: The predominance of PDE4 over PDE3 is a peculiarity of hiPSC-CMs and is probably an indicator of immaturity. This finding has implications for the use of hiPSC-CM as pharmacological models to investigate and assess the effects of PDE inhibitors.