The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells

  • 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.
Author:Beatrice Pflüger‑MüllerORCiDGND, James A. OoORCiDGND, Jan HeeringORCiD, Timothy WarwickORCiD, Ewgenij ProschakORCiDGND, Stefan GüntherORCiD, Mario LoosoORCiDGND, Flávia RezendeORCiDGND, Christian Fork, Gerd GeisslingerORCiDGND, Dominique Jeanette ThomasORCiDGND, Robert GurkeORCiDGND, Dieter SteinhilberORCiDGND, Marcel Holger SchulzORCiDGND, Matthias LeisegangORCiDGND, Ralf BrandesORCiDGND
Parent Title (English):Basic research in cardiology
Publisher:Steinkopff ; Springer
Place of publication:[Darmstadt u.a.] ; Berlin ; Heidelberg
Document Type:Article
Date of Publication (online):2020/04/22
Date of first Publication:2020/04/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/07/05
Tag:Anandamide; CCL2; HDAC4; Inflammation; NCoR1
Issue:3, art. 34
Page Number:16
First Page:1
Last Page:16
Open Access funding provided by Projekt DEAL.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0