PDE4抑制以Epac依赖性方式减少新内膜形成并抑制VCAM-1表达和组蛋白甲基化。,Journal of Molecular and Cellular Cardiology

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PDE4抑制以Epac依赖性方式减少新内膜形成并抑制VCAM-1表达和组蛋白甲基化。
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2015-02-03 , DOI: 10.1016/j.yjmcc.2015.01.015
Michael Lehrke ₁ , Florian Kahles ₁ , Anna Makowska ₁ , Pathricia V Tilstam ₂ , Sebastian Diebold ₁ , Judith Marx ₁ , Robert Stöhr ₁ , Katharina Hess ₁ , Elizabeth B Endorf ₃ , Dennis Bruemmer ₃ , Nikolaus Marx ₁ , Hannes M Findeisen ₄

Affiliation

磷酸二酯酶4（PDE4）活性介导血管损伤后依赖cAMP的平滑肌细胞（SMC）激活。在这项研究中，我们研究了罗氟司特对PDE4的特异性抑制作用在体外对小鼠体内股动脉的导线损伤后，在体外对SMC增殖和炎症激活以及新内膜形成的作用。在体外，罗氟司特不影响SMC增殖，但减少了TNF-α诱导的血管细胞粘附分子1（VCAM-1）的表达。cAMP效应子Epac的特异性激活而不是PKA激活模仿罗氟司特对VCAM-1表达的影响。一致地，在抑制Epac后，挽救了VCAM-1表达的减少。罗氟司特在SMC中不会改变TNF-α诱导的NFκBp65易位和VCAM-1启动子活性。然而，罗氟司特治疗和Epac激活抑制了VCAM-1启动子对激活的表观遗传组蛋白标记H3K4me2的诱导，而PKA激活则没有作用。此外，HDAC的抑制作用可阻断罗氟司特对VCAM-1表达的抑制作用。罗氟司特和Epac激活均降低了单核细胞在体外对SMC的粘附。最后，罗氟司特治疗在4周后使股动脉内膜-中膜比率降低了50％以上。总之，PDE4抑制通过一种新型的Epac依赖性机制调节VCAM-1，该机制涉及调节表观遗传成分并减少血管损伤后新内膜的形成。PDE4抑制和Epac激活可能代表了治疗血管疾病（包括动脉粥样硬化和支架内再狭窄）的新方法。

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PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.

Phosphodiesterase 4 (PDE4) activity mediates cAMP-dependent smooth muscle cell (SMC) activation following vascular injury. In this study we have investigated the effects of specific PDE4 inhibition with roflumilast on SMC proliferation and inflammatory activation in vitro and neointima formation following guide wire-induced injury of the femoral artery in mice in vivo. In vitro, roflumilast did not affect SMC proliferation, but diminished TNF-α induced expression of the vascular cell adhesion molecule 1 (VCAM-1). 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 following inhibition of Epac. TNF-α induced NFκB p65 translocation and VCAM-1 promoter activity were not altered by roflumilast in SMCs. 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. Furthermore, HDAC inhibition blocked the inhibitory effect of roflumilast on VCAM-1 expression. Both, roflumilast and Epac activation reduced monocyte adhesion to SMCs in vitro. Finally, roflumilast treatment attenuated femoral artery intima-media ratio by more than 50% after 4weeks. In summary, PDE4 inhibition regulates VCAM-1 through a novel Epac-dependent mechanism, which involves regulatory epigenetic components and reduces neointima formation following vascular injury. PDE4 inhibition and Epac activation might represent novel approaches for the treatment of vascular diseases, including atherosclerosis and in-stent restenosis.

更新日期：2015-01-30

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