BET-induced metabolic reprogramming fuels inflammation at the vascular-fat interface in mice and patients with cardiometabolic disease.

Epigenetic reading of histone marks by BET proteins is emerging as a pivotal mechanism governing gene transcription and may be implicated in cardiometabolic disease (CMD). Using vessels from mice and patients with CMD, we show that pharmacological inhibition of BET proteins by RVX-208 prevents the maladaptive crosstalk between perivascular adipose tissue (PVAT) and blood vessels. The effect of the BET inhibitor on endothelial function was more pronounced in the presence of PVAT. In mouse and human PVAT, RVX-208 rescued maladaptive transcriptional programs with a marked downregulation of hexokinase-2 (HK2). This was associated with reduced glycolysis, lipid accumulation, and secretion of pro-inflammatory cytokines. In human adipocytes, HK2 overexpression induced a pro-inflammatory phenotype fostering endothelial damage. Pharmacological inhibition of HK2 in vessels from cardiometabolic patients restored endothelial-dependent vasorelaxation. This unveiling of a BET/HK2-dependent crosstalk between PVAT and blood vessels highlights the potential of therapeutic strategies to prevent vascular damage in cardiometabolic patients.