Cyclic Nucleotide Phosphodiesterase Families as Targets to Treat Pulmonary Arterial Hypertension: Beyond PDE5 Inhibitors?

Pulmonary arterial hypertension (PAH) is a fatal disease with no cure. Until recently, most specific therapies for PAH had aimed at enhancing cyclic nucleotide (cAMP and cGMP) pathways, taking advantage of the vasorelaxant and antiproliferative properties of these key intracellular messengers. This process can be achieved by inhibiting phosphodiesterases (PDEs), which are intracellular enzymes responsible for cyclic nucleotide degradation. To date, only inhibitors of PDE type 5 (PDE5) have been approved for the treatment of PAH. Because the PDE superfamily comprises 11 families that encompass many variants, substantial experimental investigation has been conducted to assess the relevance of inhibiting other PDE families, aiming to offer therapeutic alternatives. This review synthesizes the main research work conducted on in vivo or ex vivo models, as well as on biological resources from patients. It helps provide evidence for the expression of PDE isoforms in the lung vasculature, as well as the efficacy and limitations of various pharmacological compounds tested for inhibiting pathological processes ongoing in the disease. Perspectives and suggestions for future research orientation are proposed.