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Published on: April 3, 2017
BET-induced metabolic reprogramming fuels inflammation at the vascular-fat interface in mice and patients with
Alessandro Mengozzi1, Sarah Costantino2, Alessia Mongelli3
1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Health Science Interdisciplinary Center, Sant'Anna School of Advanced Studies, Pisa, Italy.
Abstract:
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.
Insights
BET protein inhibition prevents harmful crosstalk between perivascular fat and blood vessels in cardiometabolic disease (CMD). This therapeutic strategy, targeting hexokinase-2 (HK2), shows promise for preventing vascular damage.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Epigenetics and Gene Regulation
Background:
- BET proteins regulate gene transcription via histone mark reading, potentially influencing cardiometabolic disease (CMD).
- Maladaptive crosstalk between perivascular adipose tissue (PVAT) and blood vessels contributes to vascular dysfunction in CMD.
Purpose of the Study:
- To investigate the role of BET proteins in the PVAT-blood vessel axis in CMD.
- To evaluate the therapeutic potential of BET protein inhibition (RVX-208) and its downstream effects on hexokinase-2 (HK2) in CMD.
Main Methods:
- Utilized mouse and human vascular and PVAT samples from patients with CMD.
- Administered pharmacological BET inhibitor RVX-208 and assessed its effects on gene expression, glycolysis, lipid accumulation, and inflammation.
- Investigated the role of hexokinase-2 (HK2) by overexpression in human adipocytes and inhibition in patient vessels.
Main Results:
- RVX-208 prevented maladaptive PVAT-blood vessel crosstalk, with enhanced effects on endothelial function in the presence of PVAT.
- BET inhibition downregulated HK2 in PVAT, reducing glycolysis, lipid accumulation, and pro-inflammatory cytokine secretion.
- HK2 overexpression in adipocytes promoted inflammation and endothelial damage; HK2 inhibition restored endothelial function in patient vessels.
Conclusions:
- A BET/HK2-dependent pathway mediates detrimental PVAT-blood vessel interactions in CMD.
- Targeting BET proteins and HK2 offers a potential therapeutic avenue to mitigate vascular damage in cardiometabolic patients.
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