2. Academic Validation
  3. The BET Protein Inhibitor Apabetalone Rescues Diabetes-Induced Impairment of Angiogenic Response by Epigenetic Regulation of Thrombospondin-1

The BET Protein Inhibitor Apabetalone Rescues Diabetes-Induced Impairment of Angiogenic Response by Epigenetic Regulation of Thrombospondin-1

  • Antioxid Redox Signal. 2022 Apr;36(10-12):667-684. doi: 10.1089/ars.2021.0127.
Shafeeq A Mohammed 1,  Mattia Albiero 2 3,  Samuele Ambrosini 1,  Era Gorica 1 4,  Gergely Karsai 5,  Carlo M Caravaggi 6,  Stefano Masi 7 8,  Giovanni G Camici 1 9 10,  Florian A Wenzl 1,  Vincenzo Calderone 4,  Paolo Madeddu 11,  Sebastiano Sciarretta 12 13,  Christian M Matter 1 9,  Gaia Spinetti 14,  Thomas F Lüscher 1 15,  Frank Ruschitzka 9,  Sarah Costantino 1,  Gian Paolo Fadini 2,  Francesco Paneni 1 9 10
Affiliations

Affiliations

  • 1 Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
  • 2 Department of Medicine, University of Padua, Padova, Italy.
  • 3 Veneto Institute of Molecular Medicine, Padova, Italy.
  • 4 Department of Pharmacy, University of Pisa, Pisa, Italy.
  • 5 Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
  • 6 Diabetic Foot Department, IRCCS MultiMedica, Milan, Italy.
  • 7 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • 8 Institute of Cardiovascular Science, University College London, London, United Kingdom.
  • 9 University Heart Center, Cardiology, University Hospital Zurich, Zürich, Switzerland.
  • 10 Department of Research and Education, University Hospital Zurich, Zürich, Switzerland.
  • 11 Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, United Kingdom.
  • 12 IRCCS Neuromed, Pozzilli, Italy.
  • 13 Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
  • 14 Cardiovascular Physiopathology-Regenerative Medicine Laboratory, IRCCS MultiMedica, Milan, Italy.
  • 15 Royal Brompton and Harefield Hospital Trust, London, United Kingdom.
PMID: 34913726 DOI: 10.1089/ars.2021.0127
Abstract

Aims: Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely, posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes. Results: Compared with vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high-glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the antiangiogenic molecule thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing vascular endothelial growth factor A (VEGFA) signaling, while APA prevents these detrimental changes. In diabetic mice with hind limb ischemia, epigenetic editing by APA restored the THBS1/VEGFA axis, thus improving limb vascularization and perfusion, compared with vehicle-treated Animals. Finally, epigenetic regulation of THBS1 by BRD4/H3K27ac was also reported in DM patients with PAD compared with nondiabetic controls. Innovation: This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes. Conclusions: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD. Antioxid. Redox Signal. 36, 667-684.

Keywords

BET inhibitors; angiogenesis; apabetalone; diabetes; epigenetics; peripheral artery disease.

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