TY - JOUR
T1 - Endothelial thioredoxin interacting protein (TXNIP) modulates endothelium-dependent vasorelaxation in hyperglycemia
AU - Lam, Yuen Ting
AU - Tan, Richard P.
AU - Michael, Praveesuda
AU - Yang, Nianji
AU - Dunn, Louise L.
AU - Cooke, John P.
AU - Celermajer, David S.
AU - Wise, Steven G.
AU - Ng, Martin K.C.
N1 - Funding Information:
We thank Dr. Philippa J.L. Simpson, Dr. Jun Yuan and Dr. Hong Zeng for their assistance in generating the two endothelial-specific TXNIP knockout and knockin mouse strains.
Publisher Copyright:
© 2022
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - Acetylcholine
KW - Diabetes
KW - Endothelial dysfunction
KW - Streptozotocin
KW - Thioredoxin interacting protein
KW - Vasorelaxation
KW - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
KW - Vasodilation/genetics
KW - Endothelium/metabolism
KW - Streptozocin
KW - Glucose
KW - Hyperglycemia/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Animals
KW - Thioredoxins/genetics
KW - Carrier Proteins/genetics
KW - Mice
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U2 - 10.1016/j.mvr.2022.104396
DO - 10.1016/j.mvr.2022.104396
M3 - Article
C2 - 35644243
AN - SCOPUS:85131120384
SN - 0026-2862
VL - 143
SP - 104396
JO - Microvascular Research
JF - Microvascular Research
M1 - 104396
ER -