2. Academic Validation
  3. Targeting SETD7 Rescues Diabetes-induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin 3G

Targeting SETD7 Rescues Diabetes-induced Impairment of Angiogenic Response by Transcriptional Repression of Semaphorin 3G

  • Diabetes. 2025 Feb 27:db240997. doi: 10.2337/db24-0997.
Shafeeq A Mohammed 1,  Era Gorica 1,  Mattia Albiero 2 3,  Gergely Karsai 4,  Alessandro Mengozzi 1 5 6,  Carlo Maria Caravaggi 7,  Samuele Ambrosini 1,  Stefano Masi 5 8,  Maria Cristina Vinci 9,  Omer Dzemali 1 10 11,  Gaia Spinetti 12,  Sanjay Rajagopalan 13 14,  Assam El-Osta 15 16 17,  Jaroslav Pelisek 18,  Frank Ruschitzka 1 19,  Gian Paolo Fadini 2 3,  Sarah Costantino 1 19,  Francesco Paneni 1 19
Affiliations

Affiliations

  • 1 Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of Zürich, Wagistrasse 12, Schlieren CH-8952, Switzerland.
  • 2 Department of Surgery, Oncology and Gastroenterology - University of Padova, Italy.
  • 3 Veneto Institute of Molecular Medicine, Padova, Italy.
  • 4 Institute of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich-8091, Switzerland.
  • 5 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • 6 Health Science Interdisciplinary Center, Sant'Anna School of Advanced Studies, Pisa, Italy.
  • 7 Diabetic Foot Department, IRCCS MultiMedica, Milan, Italy.
  • 8 Institute of Cardiovascular Science, University College London, London, UK.
  • 9 Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.
  • 10 Department of Cardiac Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
  • 11 Department of Cardiac Surgery, Zurich City Hospital-Triemli, Birmensdorferstrasse 497, 8055 Zurich, Switzerland.
  • 12 Cardiovascular Pathophysiology-Regenerative Medicine Laboratory, IRCCS MultiMedica, Milan, Italy.
  • 13 Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH.
  • 14 Case Western Reserve University School of Medicine, Cardiovascular Research Institute, Cleveland, OH.
  • 15 Baker Heart and Diabetes Institute, Epigenetics in Human Health and Disease Program, Melbourne, Vic, Australia.
  • 16 Department of Diabetes, Central Clinical School, Monash University, Melbourne, Vic, Australia.
  • 17 University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark.
  • 18 Department of Vascular Surgery, University Hospital Zurich, 8091 Zurich, Switzerland.
  • 19 University Heart Center, Cardiology, University Hospital Zurich, Zürich, Switzerland.
PMID: 40014026 DOI: 10.2337/db24-0997
Abstract

Revascularization strategies failed to improve outcome in diabetic (DM) patients with peripheral artery disease (PAD). Histone modifications are key modulators of gene expression and could play a role in angiogenic response. This study investigates the role of chromatin remodelling in modulating angiogenesis in DM. RNA Sequencing (RNA-seq) and angiogenic assays (cell migration and tube formation) were performed in human aortic endothelial cells (HAECs) exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48h. The expression of the Histone Methyltransferase SETD7 and its chromatin signature at histone 3 on lysine 4 (H3K4me1) were investigated by Western blot and chromatin immunoprecipitation (ChIP). Diabetic mice were treated with the SETD7 inhibitor (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation. The experimental findings were translated into two cohorts of DM patients with PAD. RNA-seq in HG-treated HAECs unveiled SETD7 as the top-ranking transcript. SETD7 upregulation was associated with increased H3K4me1 levels and defective angiogenesis. Both SETD7 depletion and (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-induced H3K4me1 enables the transcription of the angiogenesis inhibitor semaphorin- 3G (SEMA3G) by increasing chromatin accessibility to PPAR?. In diabetic mice with hindlimb ischemia, (R)-PFI-2 improved limb perfusion by suppressing SEMA3G. SETD7/SEMA3G axis was upregulated in DM patients with PAD. Of note, (R)-PFI-2 restored angiogenic properties in endothelial cells collected from DM patients. These findings show that SETD7 is a druggable epigenetic target in diabetic PAD.

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