A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis

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A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis. / Dunn, Louise L; Simpson, Philippa J L; Prosser, Hamish C; Lecce, Laura; Yuen, Gloria S C; Buckle, Andrew; Sieveking, Daniel P; Vanags, Laura Z; Lim, Patrick R; Chow, Renee W Y; Lam, Yuen Ting; Clayton, Zoe; Bao, Shisan; Davies, Michael Jonathan; Stadler, Nadina; Celermajer, David S; Stocker, Roland; Bursill, Christina A; Cooke, John P; Ng, Martin K C.

In: Diabetes, Vol. 63, No. 2, 02.2014, p. 675-87.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Dunn, LL, Simpson, PJL, Prosser, HC, Lecce, L, Yuen, GSC, Buckle, A, Sieveking, DP, Vanags, LZ, Lim, PR, Chow, RWY, Lam, YT, Clayton, Z, Bao, S, Davies, MJ, Stadler, N, Celermajer, DS, Stocker, R, Bursill, CA, Cooke, JP & Ng, MKC 2014, 'A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis', Diabetes, vol. 63, no. 2, pp. 675-87. https://doi.org/10.2337/db13-0417

APA

Dunn, L. L., Simpson, P. J. L., Prosser, H. C., Lecce, L., Yuen, G. S. C., Buckle, A., ... Ng, M. K. C. (2014). A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis. Diabetes, 63(2), 675-87. https://doi.org/10.2337/db13-0417

Vancouver

Dunn LL, Simpson PJL, Prosser HC, Lecce L, Yuen GSC, Buckle A et al. A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis. Diabetes. 2014 Feb;63(2):675-87. https://doi.org/10.2337/db13-0417

Author

Dunn, Louise L ; Simpson, Philippa J L ; Prosser, Hamish C ; Lecce, Laura ; Yuen, Gloria S C ; Buckle, Andrew ; Sieveking, Daniel P ; Vanags, Laura Z ; Lim, Patrick R ; Chow, Renee W Y ; Lam, Yuen Ting ; Clayton, Zoe ; Bao, Shisan ; Davies, Michael Jonathan ; Stadler, Nadina ; Celermajer, David S ; Stocker, Roland ; Bursill, Christina A ; Cooke, John P ; Ng, Martin K C. / A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis. In: Diabetes. 2014 ; Vol. 63, No. 2. pp. 675-87.

Bibtex

@article{0e883c1c1de345a481d245ff3e81f48f,
title = "A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis",
abstract = "Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.",
keywords = "Animals, Blood Glucose, Carrier Proteins, Cells, Cultured, Diabetes Mellitus, Experimental, Dose-Response Relationship, Drug, Endothelial Cells, Gene Expression Regulation, Gene Silencing, Glucose, Humans, Male, Mice, Muscle, Skeletal, Neovascularization, Physiologic, Signal Transduction, Thioredoxins",
author = "Dunn, {Louise L} and Simpson, {Philippa J L} and Prosser, {Hamish C} and Laura Lecce and Yuen, {Gloria S C} and Andrew Buckle and Sieveking, {Daniel P} and Vanags, {Laura Z} and Lim, {Patrick R} and Chow, {Renee W Y} and Lam, {Yuen Ting} and Zoe Clayton and Shisan Bao and Davies, {Michael Jonathan} and Nadina Stadler and Celermajer, {David S} and Roland Stocker and Bursill, {Christina A} and Cooke, {John P} and Ng, {Martin K C}",
year = "2014",
month = "2",
doi = "10.2337/db13-0417",
language = "English",
volume = "63",
pages = "675--87",
journal = "Diabetes",
issn = "0901-3652",
number = "2",

}

RIS

TY - JOUR

T1 - A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis

AU - Dunn, Louise L

AU - Simpson, Philippa J L

AU - Prosser, Hamish C

AU - Lecce, Laura

AU - Yuen, Gloria S C

AU - Buckle, Andrew

AU - Sieveking, Daniel P

AU - Vanags, Laura Z

AU - Lim, Patrick R

AU - Chow, Renee W Y

AU - Lam, Yuen Ting

AU - Clayton, Zoe

AU - Bao, Shisan

AU - Davies, Michael Jonathan

AU - Stadler, Nadina

AU - Celermajer, David S

AU - Stocker, Roland

AU - Bursill, Christina A

AU - Cooke, John P

AU - Ng, Martin K C

PY - 2014/2

Y1 - 2014/2

N2 - Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.

AB - Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.

KW - Animals

KW - Blood Glucose

KW - Carrier Proteins

KW - Cells, Cultured

KW - Diabetes Mellitus, Experimental

KW - Dose-Response Relationship, Drug

KW - Endothelial Cells

KW - Gene Expression Regulation

KW - Gene Silencing

KW - Glucose

KW - Humans

KW - Male

KW - Mice

KW - Muscle, Skeletal

KW - Neovascularization, Physiologic

KW - Signal Transduction

KW - Thioredoxins

U2 - 10.2337/db13-0417

DO - 10.2337/db13-0417

M3 - Journal article

C2 - 24198286

VL - 63

SP - 675

EP - 687

JO - Diabetes

JF - Diabetes

SN - 0901-3652

IS - 2

ER -

ID: 128974053