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

Louise L Dunn; Philippa J L Simpson; Hamish C Prosser; Laura Lecce; Gloria S C Yuen; Andrew Buckle; Daniel P Sieveking; Laura Z Vanags; Patrick R Lim; Renee W Y Chow; Yuen Ting Lam; Zoe Clayton; Shisan Bao; Michael Jonathan Davies; Nadina Stadler; David S Celermajer; Roland Stocker; Christina A Bursill; John P Cooke; Martin K C Ng

doi:10.2337/db13-0417

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

Louise L Dunn, Philippa J L Simpson, Hamish C Prosser, Laura Lecce, Gloria S C Yuen, Andrew Buckle, Daniel P Sieveking, Laura Z Vanags, Patrick R Lim, Renee W Y Chow, Yuen Ting Lam, Zoe Clayton, Shisan Bao, Michael Jonathan Davies, Nadina Stadler, David S Celermajer, Roland Stocker, Christina A Bursill, John P Cooke, Martin K C Ng

41 Citations (Scopus)

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.

Original language	English
Journal	Diabetes
Volume	63
Issue number	2
Pages (from-to)	675-87
Number of pages	13
ISSN	0901-3652
DOIs	https://doi.org/10.2337/db13-0417
Publication status	Published - Feb 2014
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db13-0417

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Dunn, L. L., Simpson, P. J. L., Prosser, H. C., Lecce, L., Yuen, G. S. C., Buckle, A., Sieveking, D. P., Vanags, L. Z., Lim, P. R., Chow, R. W. Y., Lam, Y. T., Clayton, Z., Bao, S., Davies, M. J., Stadler, N., Celermajer, D. S., Stocker, R., Bursill, C. A., Cooke, J. P., & 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

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

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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.",

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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}",

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doi = "10.2337/db13-0417",

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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

SN - 0901-3652

VL - 63

SP - 675

EP - 687

JO - Diabetes

JF - Diabetes

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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