Inhibition of phosphodiesterases 1 and 4 prevents myofibroblast transformation in Peyronie's disease

Abstract

Objectives

To investigate which phosphodiesterase (PDE) isoforms are expressed in fibroblasts isolated from the tunica albuginea (TA) of patients with Peyronie's disease (PD), and to measure the potency of PDE inhibitors in preventing transformation of these fibroblasts to profibrotic myofibroblasts.

Materials and Methods

Fibroblasts isolated from the TA of men undergoing surgery for correction of PD curvature were transformed to myofibroblasts using transforming growth factor beta-1. The expression of 21 PDE isoforms was investigated using quantitative reverse transcriptase-polymerase chain reaction and protein analysis, as were the effects of various PDE inhibitors on prevention of myofibroblast transformation. Intracellular cAMP and cGMP in the presence of PDE inhibitors were quantified using cGMP/cAMP enzyme-linked immunosorbant assay assays.

Results

We found that PDE1A, 1C, 4, 5A, 7B and 8B were expressed at mRNA and protein levels. Selective inhibitors of these enzymes prevented myofibroblast transformation in a concentration-dependent manner, with PDE1 inhibitor ITI-214 and PDE4 inhibitors roflumilast and roflumilast N-oxide showing greatest potency. ITI-214 and roflumilast N-oxide increased intracellular cAMP, but not cGMP, in a concentration-dependent manner.

Conclusions

This is the first demonstration of the expression of PDE1, 7 and 8 isoforms, and the function of PDE1 and PDE4 in human TA fibroblasts. The ability of inhibitors of these enzymes to prevent myofibroblast transformation suggests that such inhibitors can be developed to treat acute PD.