1. Endothelial thioredoxin interacting protein (TXNIP) modulates endothelium-dependent vasorelaxation in hyperglycemia.
- Author
-
Lam YT, Tan RP, Michael P, Yang N, Dunn LL, Cooke JP, Celermajer DS, Wise SG, and Ng MKC
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Glucose, Mice, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Proto-Oncogene Proteins c-akt metabolism, Streptozocin, Endothelium metabolism, Endothelium physiopathology, Hyperglycemia metabolism, Hyperglycemia physiopathology, Thioredoxins genetics, Thioredoxins metabolism, Vasodilation genetics, Vasodilation physiology
- Abstract
Endothelial dysfunction, hallmarked by an imbalance between vasoconstriction and vasorelaxation, is associated with diabetes. Thioredoxin Interacting protein (TXNIP), controlled by an exquisitely glucose sensitive gene, is increasingly recognized for its role in diabetes. However, the role of TXNIP in modulating diabetes-related endothelial dysfunction remains unclear. To elucidate the role of TXNIP, we generated two novel mouse strains; endothelial-specific TXNIP knockout (EKO) and a Tet-O inducible, endothelial-specific TXNIP overexpression (EKI). Hyperglycemia was induced by streptozotocin (STZ) treatment in floxed control (fl/fl) and EKO mice. Doxycycline (DOX) was given to EKI mice to induce endothelial TXNIP overexpression. The ablation of endothelial TXNIP improved glucose tolerance in EKO mice. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in STZ-treated fl/fl mice while this STZ impaired vasorelaxation was attenuated in EKO mice. Hyperglycemia induction of NLRP3 and reductions in Akt and eNOS phosphorylation were also mitigated in EKO mice. Overexpression of endothelial TXNIP did not impair glucose tolerance in DOX-treated EKI mice, however induction of endothelial TXNIP led to impaired vasorelaxation in EKI mice. This was associated with increased NLRP3 and reduced Akt and eNOS activation. In conclusion, deletion of endothelial TXNIP is protective against and overexpression of endothelial TXNIP induces endothelial dysfunction; thus, endothelial TXNIP plays a critical role in modulating endothelial dysfunction., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
- Full Text
- View/download PDF