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

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.