Epigenetic mechanisms underlying endothelial dysfunction in cardiovascular diseases: EZH2 as therapeutic target

In this thesis, we identified epigenetic mechanisms that modulate the endothelial transcriptome underlying EC dysfunction with a focus on the interaction of EZH2 with miRNAs and lncRNAs. We show that proper epigenetic regulation is crucial in maintaining endothelial homeostasis and, when this epigenetic regulation is disturbed, it results in EC dysfunction. We uncovered an important role for EZH2 and its concomitant epigenetic mark H3K27Me3, in which an increased EZH2 expression and activity induces EC dysfunction by modulation of the expression of endothelial-associated genes. However, throughout this thesis, we show that EZH2 seldomly directly regulates EC gene expression but rather via the involvement of other interactors, including miRNAs and lncRNAs. This highlights the complexity of this multi-layered epigenetic regulation network. Nonetheless, this thesis suggests that the inhibition of EZH2 and thereby lowering H3K27Me3 abundance in ECs may be a beneficial therapeutical approach to limit CVD development and progression. As epigenetic drugs, including EZH2 antagonists, are already available in the clinic or under clinical development, it is interesting to explore the use of these EZH2 antagonists in the context of CVDs as an intervention that addresses endothelial dysfunction.