Purchase this article with an account.
Mohammed A. Abdelsaid, Azza B. El-Remessy; Thioredoxin Interacting Protein Is Required For S-glutathionylation And Redox Regulation Of VEGF Angiogenic Signal. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5762.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Activation of VEGFR2 plays a key role in VEGF-mediated retinal angiogenesis. We recently showed that VEGF caused transient negative shift in cellular redox-state and oxidative inhibition of low molecular weight protein tyrosine phosphatase (LMW-PTP). The aim of the current study is to examine the role of thioredoxin interacting protein (TXNIP), the endogenous inhibitor of thioredoxin in regulating cellular redox-state and angiogenic response in response to VEGF in vitro and in vivo.
Retinal neovascularization was assessed in TXNIP-deficient mice (TKO), wild type (Wt) or Wt treated with the GSH-precursor, N-acetyl cysteine (NAC, 500 mg/kg) using ischemic retinopathy model. Redox-state was assessed by thioredoxin reductase (TrxR) activity and reduced-glutathione (GSH) levels. Angiogenic response and S-glutathionylation of LMW-PTP were assessed after silencing TXNIP in human retinal endothelial (HRE) cells using siRNA.
In response to hypoxia, retinas of TKO and NAC-treated mice experienced reductive stress as indicated by significant increases in the TrxR and GSH levels compared to Wt. These effects were associated with comparable levels of VEGF expression, impaired VEGFR2 activation and impaired retinal central revascularization and pathological neovascularization. In HRE cells, VEGF caused immediate activation of VEGFR2 that was associated with immediate and reversible oxidation of GSH levels, S-glutathionylation and inhibition of LMW-PTP in cells transduced with scambled but not TXNIP siRNA. Silencing TXNIP expression inhibited VEGF-mediated cell migration and tube formation in HRE cells and vascular sprouting in aortic rings.
Our results elucidated the critical role of TXNIP expression for achieving balanced redox-state to facilitate VEGF-mediated autoreceptor activation and angiogenic signal. We also identified S-glutathionylation of LMW-PTP as a molecular switch to regulate retinal angiogenesis.
This PDF is available to Subscribers Only