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.
Highlights
Endocannabinoids are unsaturated fatty acid derivatives that represent an important class of signaling lipid mediators best known for their effects in the central nervous system1 3 Vol.:(0123456789) 34 Page 2 of 16Basic Research in Cardiology (2020) 115:34[18]
To determine whether AEA is relevant for cellular gene expression, human aortic smooth muscle cells (HAoSMC) were pre-stimulated with the endocannabinoid for 150 min followed by cytokine stimulation for 90 min and subsequent gene expression analysis by RNA-Seq
This suggests that AEA impacts inflammatory signaling and chemokine induction in particular, which is reflected by the gene ontology (GO) analysis (Tables 2, 3)
Summary
Endocannabinoids are unsaturated fatty acid derivatives that represent an important class of signaling lipid mediators best known for their effects in the central nervous system1 3 Vol.:(0123456789) 34 Page 2 of 16Basic Research in Cardiology (2020) 115:34[18]. As endocannabinoids are released and taken up by different cells, these receptors can mediate autocrine and paracrine effects [10]. Numerous studies have looked into the vascular consequences of a genetic knockout or activation of different endocannabinoid receptors and producing and degrading enzymes, with focus on inflammatory responses and atherosclerosis [24, 30]. The results were complex in that no unifying picture emerged This is, in part, a consequence of the fact that the receptors all have different functions and that usually more than one endocannabinoid is produced by a cell. Depending on the presence of degrading and producing enzymes, cells can simultaneously produce 2-arachidonylglycerol (2-AG), arachidonoyl-ethanolamine (AEA), known as anandamide, palmitoylethanolamide (PEA) and oleoylethanolamine (OEA) and each of these endocannabinoids can activate multiple receptors and signaling cascades
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