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PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.
J Mol Cell Cardiol. 2015 Apr; 81:23-33.JM

Abstract

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.

Authors+Show Affiliations

Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: mlehrke@ukaachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: florian.kahles@rwth-aachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: amakowska@ukaachen.de.Institute of Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: ptilstam@ukaachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: sdiebold@ukaachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: judith.marx@rwth-aachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: rstoehr@ukaachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: khess@ukaachen.de.Division of Cardiovascular Medicine, Gill Heart Institute, Saha Cardiovascular Research Center, University of Kentucky, College of Medicine, 741 South Limestone, Lexington, KY 40536-0509, USA. Electronic address: brydenheywood@uky.edu.Division of Cardiovascular Medicine, Gill Heart Institute, Saha Cardiovascular Research Center, University of Kentucky, College of Medicine, 741 South Limestone, Lexington, KY 40536-0509, USA. Electronic address: dennis.bruemmer@uky.edu.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany. Electronic address: nmarx@ukaachen.de.Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany; Department of Cardiology and Angiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany. Electronic address: hannes.findeisen@ukmuenster.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25640159

Citation

Lehrke, Michael, et al. "PDE4 Inhibition Reduces Neointima Formation and Inhibits VCAM-1 Expression and Histone Methylation in an Epac-dependent Manner." Journal of Molecular and Cellular Cardiology, vol. 81, 2015, pp. 23-33.
Lehrke M, Kahles F, Makowska A, et al. PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner. J Mol Cell Cardiol. 2015;81:23-33.
Lehrke, M., Kahles, F., Makowska, A., Tilstam, P. V., Diebold, S., Marx, J., Stöhr, R., Hess, K., Endorf, E. B., Bruemmer, D., Marx, N., & Findeisen, H. M. (2015). PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner. Journal of Molecular and Cellular Cardiology, 81, 23-33. https://doi.org/10.1016/j.yjmcc.2015.01.015
Lehrke M, et al. PDE4 Inhibition Reduces Neointima Formation and Inhibits VCAM-1 Expression and Histone Methylation in an Epac-dependent Manner. J Mol Cell Cardiol. 2015;81:23-33. PubMed PMID: 25640159.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner. AU - Lehrke,Michael, AU - Kahles,Florian, AU - Makowska,Anna, AU - Tilstam,Pathricia V, AU - Diebold,Sebastian, AU - Marx,Judith, AU - Stöhr,Robert, AU - Hess,Katharina, AU - Endorf,Elizabeth B, AU - Bruemmer,Dennis, AU - Marx,Nikolaus, AU - Findeisen,Hannes M, Y1 - 2015/01/30/ PY - 2014/08/31/received PY - 2015/01/21/revised PY - 2015/01/22/accepted PY - 2015/2/3/entrez PY - 2015/2/3/pubmed PY - 2016/3/5/medline KW - Epac KW - Epigenetic KW - PDE4 KW - Roflumilast KW - Smooth muscle cells KW - VCAM-1 SP - 23 EP - 33 JF - Journal of molecular and cellular cardiology JO - J Mol Cell Cardiol VL - 81 N2 - 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/25640159/PDE4_inhibition_reduces_neointima_formation_and_inhibits_VCAM_1_expression_and_histone_methylation_in_an_Epac_dependent_manner_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(15)00028-0 DB - PRIME DP - Unbound Medicine ER -