TY  - JOUR
A1  - Pflüger‑Müller, Beatrice
A1  - Oo, James A.
A1  - Heering, Jan Peter
A1  - Warwick, Timothy
A1  - Proschak, Ewgenij
A1  - Günther, Stefan
A1  - Looso, Mario
A1  - Rezende Felipe, Flávia Figueiredo de
A1  - Fork, Christian
A1  - Geisslinger, Gerd
A1  - Thomas, Dominique Jeanette
A1  - Gurke, Robert
A1  - Steinhilber, Dieter
A1  - Schulz, Marcel Holger
A1  - Leisegang, Matthias
A1  - Brandes, Ralf
T1  - The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells
T2  - Basic research in cardiology
N2  - Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
KW  - Anandamide
KW  - HDAC4
KW  - NCoR1
KW  - Inflammation
KW  - CCL2
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63783
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-637834
SN  - 1435-1803
N1  - Open Access funding provided by Projekt DEAL.
VL  - 115.2020
IS  - 3, art. 34
SP  - 1
EP  - 16
PB  - Steinkopff ; Springer
CY  - [Darmstadt u.a.] ; Berlin ; Heidelberg
ER  -