Pde4d, encoding phosphodiesterase 4D, is a key enzyme in the PDE4 family. It catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing fundamental roles in various physiological processes, such as brain function, immune cell activation, and neutrophil infiltration. It is also involved in cognitive, learning, and memory consolidation processes, as well as in cancer development [1].

In heart-related studies, global and conditional cardiac-specific heterozygous Pde4d knockout mice and adeno-associated virus serotype 9-Pde4d overexpression models were used. These models showed that Pde4d upregulation was observed in failing hearts. In vitro, isoproterenol stimulation increased Pde4d expression. Pde4d overexpression induced oxidative stress, mitochondrial damage, and cardiomyocyte hypertrophy by inhibiting the cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while Pde4d silencing or inhibition with a Pde4 inhibitor ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo, Pde4d inhibition or cardiac-specific Pde4d haploinsufficiency ameliorated cardiac hypertrophy and heart failure caused by ISO injection or TAC [3].

In conclusion, Pde4d is crucial in regulating cAMP-related signaling in multiple biological processes. The use of gene knockout and overexpression mouse models has revealed its role in heart failure, suggesting that Pde4d inhibition could be a novel therapeutic strategy for heart failure. Additionally, Pde4d is associated with neurodegenerative diseases, stroke, and cancer, highlighting its potential as a multipurpose pharmacological target [1,2,3,4,5,6].