Regulation of murine cardiac function by phosphodiesterases type 3 and 4

Cyclic nucleotide phosphodiesterases (PDEs) encompass a large group of enzymes that regulate intracellular levels of two-second messengers, cAMP and cGMP, by controlling the rates of their degradation. More than 60 isoforms, subdivided into 11 gene families (PDE1-11), exist in mammals with at least six families (PDE1-5 and PDE8) identified in mammalian hearts. The two predominant families implicated in regulating contraction strength of the heart are PDE3 and PDE4. Studies using transgenic models in combination with family-specific PDE inhibitors have demonstrated that PDE3A, PDE4B, and PDE4D isoforms regulate cardiac contractility by modulating cAMP levels in various subcellular compartments. These studies have further uncovered contributions of PDE4B and PDE4D in preventing ventricular arrhythmias.

► Phosphodiesterases (PDEs) regulate cAMP and cGMP levels in cardiomyocytes.
► PDE3 and PDE4 are the most important isoforms in regulating cardiac function.
► PDE3A and PDE4D control cAMP at the level of sarcoplasmic reticulum.
► PDE4B regulates cAMP at the level of the plasma membrane.
► Loss of PDE4B and PDE4D leads increased incidence of ventricular arrhythmias.