Pde4b, a member of the phosphodiesterase 4 (PDE4) family, hydrolyzes intracellular cyclic adenosine monophosphate (cAMP) [1,2]. As a key negative regulator of cardiac β -adrenergic receptor stimulation, it is involved in cAMP-related signaling pathways, which are crucial for various biological processes in different tissues [2]. Genetic models, such as KO/CKO mouse models, have been instrumental in studying its functions.

In acute myocardial infarction, PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after myocardial ischemia-reperfusion (MI/R). PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, it mediated neutrophil-endothelial cell interaction and PKA-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. It also promoted coronary microcirculatory obstruction and vascular permeability in MI/R [1].

In heart failure, PDE4B protein was decreased in human failing hearts. Moderate overexpression of PDE4B in transgenic mouse lines or via adeno-associated virus serotype 9 encoding PDE4B protected against systolic dysfunction, hypertrophy, apoptosis, and fibrosis induced by chronic isoproterenol treatment or transverse aortic constriction [2].

In idiopathic pulmonary fibrosis, BI 1015550, a preferential PDE4B inhibitor, showed anti-inflammatory and antifibrotic potential in mouse models and in human fibroblasts from patients with IPF [3].

In conclusion, Pde4b is critically involved in multiple biological processes related to inflammation, microvascular function, and cardiac remodeling. Studies using KO/CKO mouse models have revealed its role in diseases such as acute myocardial infarction, heart failure, and idiopathic pulmonary fibrosis, highlighting its potential as a therapeutic target in these disease areas.