Susanne Viktoria Schmidt

2-arachidonoylglycerol (2-AG) is an endogenous modulator of inflammatory processes. Recent studies demonstrate its key role in inflammatory cardiovascular diseases, such as atherosclerosis and left ventricular remodelling. However, whether 2-AG acts as a pro- or anti-inflammatory agent in cardiovascular inflammation is a matter of controversial debate. CD14 ⁺ primary human monocytes were treated with 2-AG. Differentially expressed genes were determined by mRNA sequencing and used for bioinformatics analysis of changes in myeloid cell functions and cell signalling pathways. Additionally, we quantified cytokines and mediators involved in cardiac remodelling by multiplexing assays. Human monocytes responded to the treatment with 2-AG by inducing a pro-inflammatory cellular program. The top upregulated hallmark pathways were TNFα signalling via the NF-κB pathway, the inflammatory response and IL-6 signalling, illustrating the pro-inflammatory mode of action of 2-AG. These data were validated at the protein level in the supernatants of stimulated cells using multiplexing assays. Based on these in-vitro results, we examined blood samples from patients during acute and chronic coronary syndromes. By sampling blood from both the periphery and the culprit coronary artery, we observed a trend towards higher local concentrations of the cardiac remodelling factors Galectin-3, Osteopontin, and IP-10 in the coronary arteries of patients presenting with acute coronary syndrome compared with other groups. The levels of these remodelling factors correlate positively with 2-AG levels. Taken together, our data suggest that 2-AG acts as a pro-inflammatory agent in myocardial infarction and LV remodelling.

Individual patients with H3K27M-mutant DMG treated with ONC201.

ONC201 dosage chart for patients younger than 18 years of age.

Individual cases from historical control datasets.

Upregulated and downregulated metabolites in DIPG007 cells treated with ONC201 versus vehicle.

VST-transformed gene expression values for all samples and protein-coding genes.

GSEA analysis of genes with significantly lower chromatin accessibility at promoters and enhancers and reduced gene expression in DIPG007 cells treated with ONC201 versus vehicle.

Summary of historical control datasets.

Expression values, Spearman’s correlation coefficient, and GSEA of genes associated with positive or negative correlation with radiographic response to ONC201 treatment.