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- W2139139641 abstract "Introduction: Upregulation of phosphodiesterase 4 (PDE4) activity causes cAMP-dependent vascular smooth muscle cell (VSMC) activation at sites of vascular inflammation and tissue remodeling. Hypothesis: PDE4 inhibition reduces VSMC activation and neointima formation following vascular injury. Methods: C57BL/6 mice (n=16) treated with roflumilast underwent guide wire-induced endothelial denudation injury of the femoral artery. Neointima formation was quantified after 4 weeks. In vitro, we analyzed the effects of roflumilast on VSMC proliferation and inflammation. Results: Roflumilast treatment attenuated neointima formation by 40% (17252 ± 2315 vs. 10119 ± 738 μm 2 , p=0,02) and femoral artery intima-media ratio by more than 50% (2,76 ± 0,32 vs. 1,35 ± 0,25 ,p=0,005). In vitro, roflumilast did not affect VSMC proliferation, but diminished TNF-α induced expression of the inflammatory marker vascular cell adhesion molecule 1 (VCAM-1) by 60% (p<0.05). Specific activation of the cAMP effector Epac, but not PKA activation mimicked the effects of roflumilast on VCAM-1 expression. Consistently, the reduction of VCAM-1 expression was rescued in the presence of the Epac inhibitor ESI-09 and following siRNA mediated knockdown of Epac1. TNF-α induced NFκB p65 translocation and VCAM-1 promotor activity were not altered by roflumilast in VSMCs. However, Roflumilast treatment and Epac activation repressed the induction of the activating epigenetic histone mark H3K4me2 at the VCAM-1 promoter, while PKA activation showed no effect. In accordance with the reduction of VCAM-1 in vitro, roflumilast treated mice displayed decreased expression of VCAM-1 and the macrophage markers F4/80 and CD68 during neointima formation. Consistently, immunohistochemical analysis of the vessel wall showed reduced Mac2 staining, indicating decreased macrophage accumulation after vascular injury. Conclusions: PDE4 inhibtion reduces neointimal hyperplasia after vascular injury and regulates VCAM-1 through a novel Epac-dependent mechanism, which modulates specific histone methylation patterns. PDE4 inhibition might represent a novel approach for the treatment of vascular diseases, including atherosclerosis and in-stent restenosis." @default.
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- W2139139641 date "2014-05-01" @default.
- W2139139641 modified "2023-09-27" @default.
- W2139139641 title "Abstract 547: PDE4 Inhibition Protects Against Neointimal Hyperplasia and Diminishes VCAM-1 Expression and Histone Methylation Through an Epac-Dependent Pathway" @default.
- W2139139641 doi "https://doi.org/10.1161/atvb.34.suppl_1.547" @default.
- W2139139641 hasPublicationYear "2014" @default.
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