Regulation of cardiac contractility and hypertrophy by cGMP nanodomains

cGMP is critically involved in the regulation of multiple intracellular events in cardiomyocytes which are crucial for both normal function and disease such as heart failure. Phosphodiesterases (PDEs), as the enzymes which degrade cyclic nucleotides can be well targeted therapeutically and have been in focus of investigation because they can actively shape subcellular cGMP nanodomains linked to functional responses. While lots of studies focused on PDE5 and PDE9 as typical cGMP degrading PDEs, the role of dual-specific PDE1 and PDE3 in terms of cGMP regulation has been mostly ignored. In our recent studies, we have looked at cGMP hydrolysis by PDE1 and PDE3 and how its regulates cardiomyocyte contractility and hypertrophy via subcellular nanodomains using live cell imaging. We found that PDE1 inhibition amplifies cGMP pools generated by the NO-dependent but not the particulate guanylyl cyclase. Furthermore, it improves cardiomyocyte relaxation when combined with NO-donors or natriuretic peptides. PDE3, which is often referred to as cGMP inhibited PDE, contributes substantially to cGMP hydrolysis in these cells und undergoes posttranslational regulation upon ischemic injury which could impact the development of cardiac hypertrophy and the effects of cGMP elevating drugs.