For anyone managing cardiovascular risk, the conventional focus on blood lipids and blood pressure may be missing a critical upstream driver: the metabolically active fat wrapped around blood vessels. New mechanistic evidence suggests this perivascular adipose tissue communicates with the vessel wall through an epigenetic-metabolic circuit that can be pharmacologically interrupted — potentially rewriting how cardiometabolic disease is treated.
The research centers on BET proteins, epigenetic readers that decode histone acetylation marks to regulate gene transcription. Using vascular tissue from both a mouse model and patients with established cardiometabolic disease, investigators found that blocking BET proteins with the compound RVX-208 disrupted a damaging dialogue between perivascular adipose tissue and adjacent blood vessels. The inhibitor's benefit on endothelial function was amplified specifically when perivascular fat was present. Mechanistically, BET inhibition sharply reduced expression of hexokinase-2 (HK2), the rate-limiting glycolytic enzyme, in both mouse and human perivascular fat. Lower HK2 activity translated into reduced glycolytic flux, less lipid accumulation, and a blunted release of pro-inflammatory cytokines. Critically, HK2 overexpression alone in human adipocytes was sufficient to trigger an inflammatory phenotype that damaged endothelial cells, and direct HK2 inhibition in vessels from cardiometabolic patients restored endothelium-dependent vasorelaxation.
This BET/HK2 axis is a compelling addition to a growing literature linking epigenetic dysregulation to metabolic-inflammatory crosstalk. RVX-208, also known as apabetalone, has previously shown cardiovascular signal in clinical trials, lending translational credibility here. The identification of HK2 as the pivotal downstream effector is notable because it connects epigenetic control to the Warburg-like metabolic reprogramming increasingly observed in inflamed adipose tissue. Key limitations include the reliance on ex vivo vascular preparations rather than in vivo endpoints, and the absence of long-term safety data for HK2 inhibition in a systemic context. Still, the dual-species validation using actual patient tissue elevates this beyond typical rodent-only mechanistic work, making it an incrementally important and potentially actionable finding for cardiovascular medicine.
