Pde4d, a member of the phosphodiesterase 4 (PDE4) family, encodes an enzyme that catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis. PDE4 enzymes are involved in numerous physiological processes, such as 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].

In cardiac studies, global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression models were used. PDE4D upregulation was observed in failing hearts. PDE4D overexpression induced oxidative stress, mitochondrial damage, and cardiomyocyte hypertrophy by inhibiting the cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway and decreasing PINK1/Parkin-mediated mitophagy. Conversely, PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy in vitro, and roflumilast or cardiac-specific PDE4D haploinsufficiency improved cardiac hypertrophy and heart failure in vivo [2]. In mice with angiotensin II (AngII)-induced hypertensive heart disease, increased localization of PDE4D around β1-and β2-adrenergic receptors (β-ARs) in the sinoatrial node (SAN) led to impaired heart rate (HR) responses to β-AR stimulation. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation [3].

In conclusion, Pde4d is crucial in regulating cAMP-related physiological processes. Studies using gene knockout and overexpression mouse models have revealed its role in heart-related diseases, such as cardiac hypertrophy, heart failure, and hypertensive heart disease. These findings suggest that targeting Pde4d could be a potential therapeutic strategy for these conditions.