Targetingโ S-Nitrosoglutathione Reductase Improves Vascular Function in Diabetic Rodent Models
Diabetic vascular complications represent a significant clinical challenge, often proving โฃresistant โto conventional โglucose-lowering treatments.โฃ Recent research has โidentified S*-nitrosoglutathione reductaseโฃ (GSNOR) as a key โcontributor toโฃ these complications, presenting a novel therapeutic target. Utilizing unbiased proteomics, researchers discovered elevated GSNOR levels in the endothelial cells of patients with typeโค 2 diabetes, and confirmed thisโ upregulation in both streptozotocin (STZ)-induced type 1 diabetes and *db/db type 2โข diabetes mouse models.
To investigate โGSNOR’s role,theโข 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 โstudies further โขdemonstrated โthat GSNOR โdeficiency 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 theseโ effects โappears independent of GSNOR’s enzymatic activity. The study revealed that GSNOR directly binds to the transcription โฃfactor โคETS-related gene (ERG), triggeringโ its removal โคfrom โthe nucleus โviaโ interaction โwith chromosome region maintenance 1.
Based on these โคfindings, the โฃresearchers developed NYY-001, โคan orally available compound โdesigned toโ specifically โขdisrupt the GSNOR-ERG interaction. Cryo-electron โคmicroscopy confirmed the direct binding of NYY-001 to GSNOR. โค Treatment with NYY-001 in both STZ-induced type 1 diabetes and db/db โ type 2 โฃdiabetes mouse โmodels led to โenhanced postischemic neovascularizationโ and restoration โof vascular โขpermeability in peripheralโ vasculature.
Theseโข results establishโ a critical mechanistic โฃlink between the GSNOR-ERG complex and โthe advancement of diabetic vascular complications, โคand position NYY-001 as a promising therapeutic โฃcandidate for this challenging condition.