Transcriptional regulation of Hexokinase-2 by BRD4 drives perivascular adipose tissue meta-inflammation in cardiometabolic disease

Selected Abstract – Spring Meeting 2024

Alessandro Mengozzi
Department of Clinical and Experimental Medicine, University of Pisa, Italy, and Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland, and Scuola Superiore Sant'Anna, Pisa, Italy
Sarah Costantino
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland, and University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland
Alessia Mongelli
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland
Emiliano Duranti
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Shafeeq A. Mohammed
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland
Era Gorica
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland
Marialucia Telesca
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland
Silvia Armenia
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Federica Cappelli
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Christian M. Matter
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland, and University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland
Stefano Taddei
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Stefano Masi
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Frank Ruschitzka
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland, and University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland
Agostino Virdis
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Francesco Paneni
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland, and University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland

Abstract

Aim: To investigate BRD4-related transcriptional programmes in mouse and human models of cardiometabolic disease.
Methods: Small arteries (0.1-0.3 mm) dissected from visceral fat biopsies from healthy subjects (n=16) and patients with obesity and hypertension (n=16) were mounted on a pressurized myograph to assess the acute ex-vivo effects of BRD4 inhibition on vascular function. Vasorelaxation to acetylcholine and acetylcholine+L-NAME was evaluated, in the presence or in the absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 and with selective anti-inflammatory and anti-metabolic drugs. A cardiometabolic mouse (high-fat diet+L-NAME supplementation) was orally administered RVX-208 (150 mg/kg) to test in vivo effect of chronic BRD4 inhibition. ROS and nitric oxide were assessed by confocal microscopy; protein and gene expression by Western blot and qPCR. Transcriptional changes upon BRD4 inhibition were investigated by a custom PCR array, confirmed by ChIP, and characterised by metabolomics, lipidomics and mitochondrial swelling.
Results: Endothelial-dependent vasorelaxation and vascular and perivascular TNF-alpha, IL-1beta, IL-6 were altered in cardiometabolic patients and mice. RVX-208 substantially attenuated ex-vivo vascular dysfunction, with an impact greater than anti-IL-1beta, anti-IL-6 receptor and anti-TNF-alpha. The effect was more pronounced in vessels with intact PVAT, suggesting a restoration of the PVAT anti-contractile phenotype. Gene expression profiling in PVAT unveiled hexokinase-2 (HK2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - as the top downregulated gene by RVX-208 treatment. Increased binding of BRD4 to HK2 promoter in PVAT samples from cardiometabolic mice was confirmed by ChIP assays. Metabolomics assays further validated the findings by demonstrating a glycolytic shift in PVAT under disease conditions. Finally, ex vivo selective inhibition of HK2 rescued vascular dysfunction.
Conclusion: Targeting the deleterious BRD4-HK2 interplay restores cardiometabolic vascular dysfunction via reversal of the PVAT meta-inflammatory shift, highlighting a novel potential target to fight cardiometabolic pandemics.

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