Targeting S-Nitrosoglutathione Reductase Improves Vascular Function in Diabetic Rodent Models
Diabetic vascular complications represent a significant clinical challenge, often proving resistant to conventional glucose-lowering treatments. Recent research has identified S*-nitrosoglutathione reductase (GSNOR) as a key contributor to these complications, presenting a novel therapeutic target. Utilizing unbiased proteomics, researchers discovered elevated GSNOR levels in the endothelial cells of patients with type 2 diabetes, and confirmed this upregulation in both streptozotocin (STZ)-induced type 1 diabetes and *db/db type 2 diabetes mouse models.
To investigate GSNOR’s role,the researchers genetically deleted Gsnor specifically in endothelial cells of STZ-induced type 1 diabetic mice. This ablation resulted in improved angiogenesis, preserved vascular permeability, and enhanced vasodilation. In vitro studies further demonstrated that GSNOR deficiency protected endothelial cells from high glucose-induced dysfunction, evidenced by restored tube formation, increased spheroid sprouting, maintained barrier integrity, and reduced permeability.
Importantly, the mechanism driving these effects appears independent of GSNOR’s enzymatic activity. The study revealed that GSNOR directly binds to the transcription factor ETS-related gene (ERG), triggering its removal from the nucleus via interaction with chromosome region maintenance 1.
Based on these findings, the researchers developed NYY-001, an orally available compound designed to specifically disrupt the GSNOR-ERG interaction. Cryo-electron microscopy confirmed the direct binding of NYY-001 to GSNOR. Treatment with NYY-001 in both STZ-induced type 1 diabetes and db/db type 2 diabetes mouse models led to enhanced postischemic neovascularization and restoration of vascular permeability in peripheral vasculature.
These results establish a critical mechanistic link between the GSNOR-ERG complex and the advancement of diabetic vascular complications, and position NYY-001 as a promising therapeutic candidate for this challenging condition.
