The phosphodiesterase 4 inhibitor roflumilast attenuates neointima formation and vascular smooth muscle cell inflammation

Purpose: PDE-4 inhibitors provide a novel approach to treat inflammatory diseases. In this study we have investigated the effects of PDE-4 inhibition on vascular smooth muscle cell activation and neointima formation. Methods: C57BL/6 mice treated with the PDE-4 inhibitor Roflumilast (added to the diet, 21 mg/kg) underwent guide wire induced endothelial denudation of the femoral artery. Neointima formation was quantified after 4 weeks. In vitro we analyzed the effects of Roflumilast treatment on vascular smooth muscle cell (VSMC) proliferation and inflammatory activation. Results: Roflumilast treatment reduced neointima formation and femoral artery intima-media ratio by more than 50% (p<0.01). In vitro Roflumilast did not affect VSMC proliferation analyzed by cell counting, BrdU inkorporation and cell cycle analysis. However, it significantly diminished expression of the inflammatory marker vascular cell adhesion molecule 1 (VCAM-1) by 60% (p<0.05) in TNF-α treated VSMC. The observed VCAM-1 repression could be reproduced through specific activation of the cAMP effector Epac, while PKA activation showed no significant effect. In contrast to PKA activation, Roflumilast treatment and Epac activation resulted in decreased induction of histone H3-lysine trimethylation (H3K4me3) at the VCAM-1 promoter. Conclusions: Inhibition of PDE-4 reduces neointima formation following endothelial denudation and attenuates VSMC inflammatory activation in vitro. This observation might be regulated through an Epac-dependent mechanism which modulates specific histone methylation patterns.