title: PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.
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: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: mlehrke@ukaachen.de.
authors: Michael
authors: M
authors: Lehrke
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: florian.kahles@rwth-aachen.de.
authors: Florian
authors: F
authors: Kahles
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: amakowska@ukaachen.de.
authors: Anna
authors: A
authors: Makowska
authors: Institute of Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: ptilstam@ukaachen.de.
authors: Pathricia V
authors: PV
authors: Tilstam
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: sdiebold@ukaachen.de.
authors: Sebastian
authors: S
authors: Diebold
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: judith.marx@rwth-aachen.de.
authors: Judith
authors: J
authors: Marx
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: rstoehr@ukaachen.de.
authors: Robert
authors: R
authors: Stöhr
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: khess@ukaachen.de.
authors: Katharina
authors: K
authors: Hess
authors: 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.
authors: Elizabeth B
authors: EB
authors: Endorf
authors: 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.
authors: Dennis
authors: D
authors: Bruemmer
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: nmarx@ukaachen.de.
authors: Nikolaus
authors: N
authors: Marx
authors: Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 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.
authors: Hannes M
authors: HM
authors: Findeisen
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics* / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D006657:Histones; D058988:Phosphodiesterase 4 Inhibitors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C424423:Roflumilast; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C095813:Pde4a protein, mouse
keywords: Epac; Epigenetic; PDE4; Roflumilast; Smooth muscle cells; VCAM-1