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 journal › Journal article › Research › peer-review
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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