Recently roflumilast has been approved as
Recently, roflumilast has been approved as the first selective PDE4 inhibitor for the treatment of chronic obstructive pulmonary disease (COPD) . Roflumilast has been suggested to target several different pathogenetic mechanisms, including inflammation, fibrotic, emphysematous and vascular remodeling, as well as oxidative stress in COPD. The introduction of roflumilast into clinical practice has therefore provided a unique therapeutic opportunity to target PDE4 inhibition during various diseases mediated by inflammation and tissue remodeling , . In the present study, we have investigated the effect of selective PDE4 inhibition by roflumilast on SMC proliferation and inflammation as well as neointima formation in vivo.
Materials and methods
Discussion Vascular smooth muscle 3-isomangostin undergo a phenotypic switch at sites of vascular injury, resulting in a phenotype that promotes vascular inflammation and remodeling . During this phenotypic switch PDE4 activity has been suggested to bolster SMC activation by inhibiting cAMP signaling . In this study, we report that pharmacological inhibition of PDE4 activity by roflumilast provides a potent inhibition of TNF-α-induced VCAM-1 expression and monocyte adhesion. Furthermore, using Epac specific agonists and inhibitors, we could establish that roflumilast-dependent VCAM-1 inhibition is mediated through Epac rather than PKA. Both roflumilast treatment and Epac activation resulted in a significant reduction of the activating histone mark H3K4me2 at the VCAM-1 promoter. Finally, roflumilast significantly reduced neointima formation and intima/media ratio in vivo. Collectively, our data identify PDE4 inhibition and Epac activation as a promising mechanism to target vascular inflammation and remodeling and link cAMP-Epac signaling to epigenetic regulation of cell adhesion molecule expression in SMCs. Several studies have previously demonstrated that activation of cAMP signaling supports a contractile and quiescent phenotype in SMC , , , . However, following vascular injury and growth factor or cytokine stimulation, SMCs are desensitized to cAMP-signaling as a consequence of increased cAMP hydrolysis by PDEs which leads to SMC activation and phenotypic switch , . While acute pharmacologic increase of cAMP levels inhibits SMC activation, this effect was found to be lost after prolonged cAMP application presumably as consequence of increased PDE-dependent cAMP hydrolysis . In synthetic SMCs this desensitization is conferred through a shift from PDE3 to PDE4 activity with upregulation of specific PDE4 isoforms , , , . Therefore, selective PDE4 inhibition has been suggested to specifically target activated SMC-driven vascular remodeling . Proliferation of medial SMCs activated by growth factors and inflammatory cytokines constitutes a major determinant of vascular remodeling and neointima formation following vascular injury . While previous studies have repeatedly confirmed a growth inhibitory effect of cAMP-elevating agents in SMCs , , studies investigating the effects of PDE4 inhibition on SMC proliferation have yielded inconclusive results , , . In this study, we have observed no direct inhibition of SMC proliferation following roflumilast dependent PDE4 inhibition. Overall, current evidence suggests that direct antiproliferative effects of specific PDE4 inhibition play, if any, only a minor role for the decreased neointima formation observed by roflumilast treatment. However, as SMC proliferation is the major contributor to neointima formation, roflumilast has to exert indirect antiproliferative effects on SMCs in vivo at some point. Therefore, roflumilast might exhibit an indirect antiproliferative effect through reduced inflammation in the vascular wall and subsequent activation of SMCs.
Conflict of interest