2. Academic Validation
  3. The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells

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

  • Basic Res Cardiol. 2020 Apr 22;115(3):34. doi: 10.1007/s00395-020-0793-3.
Beatrice Pflüger-Müller 1 2,  James A Oo 1 2,  Jan Heering 3,  Timothy Warwick 1 2,  Ewgenij Proschak 4,  Stefan Günther 5,  Mario Looso 5,  Flávia Rezende 1 2,  Christian Fork 1 2,  Gerd Geisslinger 3 6,  Dominique Thomas 6,  Robert Gurke 3 6,  Dieter Steinhilber 3 4,  Marcel Schulz 7,  Matthias S Leisegang 1 2,  Ralf P Brandes 8 9
Affiliations

Affiliations

  • 1 Fachbereich Medizin, Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
  • 2 German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt, Germany.
  • 3 Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 60438, Frankfurt, Germany.
  • 4 Institute of Pharmaceutical Chemistry, Goethe-University, 60438, Frankfurt, Germany.
  • 5 Max-Planck-Institute for Heart- and Lung Research (MPI-HLR), 61231, Bad Nauheim, Germany.
  • 6 Faculty of Medicine, Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, 60590, Frankfurt, Germany.
  • 7 Vascular Research Centre, Goethe-University, 60596, Frankfurt, Germany.
  • 8 Fachbereich Medizin, Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. brandes@vrc.uni-frankfurt.de.
  • 9 German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt, Germany. brandes@vrc.uni-frankfurt.de.
PMID: 32323032 DOI: 10.1007/s00395-020-0793-3
Abstract

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.

Keywords

Anandamide; CCL2; HDAC4; Inflammation; NCoR1.

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