Pde4d, encoding Phosphodiesterases 4D, is part of the PDE4 family. PDE4 enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in numerous physiological processes, including brain function, immune cell activation, and neutrophil infiltration. PDE4D, in particular, plays a fundamental role in cognitive, learning and memory consolidation processes, as well as in cancer development [1].

Global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression models were used to study its role in the heart. PDE4D upregulation was seen in failing hearts. In vitro, PDE4D overexpression induced oxidative stress, mitochondrial damage, and cardiomyocyte hypertrophy by inhibiting cAMP-PKA-CREB-Sirtuin1-mediated mitophagy. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo, ISO injection or TAC-induced cardiac hypertrophy and HF were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency [2].

In conclusion, PDE4D is a key player in multiple physiological processes, with a particularly significant role in cognitive function, cancer development, and cardiac pathophysiology. The use of gene knockout and overexpression mouse models has provided valuable insights into its role in cardiac hypertrophy and heart failure, suggesting that PDE4D inhibition could be a novel therapeutic strategy for these conditions [1,2].