The emerging role of the thioredoxin system in angiogenesis - PubMed (original) (raw)

Review

The emerging role of the thioredoxin system in angiogenesis

Louise L Dunn et al. Arterioscler Thromb Vasc Biol. 2010 Nov.

Abstract

Although there have been a multitude of studies, the mechanisms of angiogenesis remain incompletely understood. Increasing evidence suggests that cellular redox homeostasis is an important regulator of angiogenesis. The thioredoxin (TRX) system functions as an endogenous antioxidant that can exert influence over endothelial cell function via modulation of cellular redox status. It has become apparent that the cytosolic TRX1 isoform participates in both canonical and novel angiogenic signaling pathways and may represent an avenue for therapeutic exploitation. Recent studies have further identified a role for the mitochondrial isoform TRX2 in ischemia-induced angiogenesis. TRX-interacting protein (TXNIP) is the endogenous inhibitor of TRX redox activity that has been implicated in growth factor-mediated angiogenesis. As TXNIP is strongly induced by glucose, this molecule could be of consequence to disordered angiogenesis manifest in diabetes mellitus. This review will focus on data implicating the TRX system in endothelial cell homeostasis and angiogenesis.

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Figures

Figure 1

Figure 1. The Thioredoxin System

(A) Thioredoxin (TRX) in the oxidized (TRX-S2) or reduced (TRX-(SH)2) state. In the reduced state, TRX directly reduces disulfides in oxidized substrate proteins (PR--S2). The resultant oxidation of TRX in this process is reversible and maintained by thioredoxin reductase (TRXR) and the electron donor NADPH. (B) Thioredoxin interacting protein (TXNIP) can form a mixed disulfide with reduced thioredoxin-1 (TRX1), inhibiting the ability of TRX1 to reduce disulfides of other protein substrates and/or undergo reversible oxidation.

Figure 2

Figure 2. The Thioredoxin System and Angiogenesis

Thioredoxin-1 (TRX1) and its endogenous inhibitor Thioredoxin Interacting Protein (TXNIP) are involved in multiple signaling pathways and cellular processes that confluence in mediation of angiogenesis. The TRX1/TXNIP system can modulate cell growth and proliferation by transcriptional mechanisms such as redox factor-1 (REF1) and NF-kB, JAB1/p27kip1 translocation, DNA synthesis via ribonucleotide reductase and energy metabolism/glycolysis through reductive inhibition of PTEN. Akt signaling facilitates cell survival. Apoptosis is modulated through the interaction of either cytosolic TRX1 or mitochondrial thioredoxin-2 (TRX2) with apoptosis signaling kinase-1 (ASK1) and competitive inhibition by TXNIP. In endothelial cells TRX1 prevents von Hippel-Lindau (pVHL) mediated degradation of the transcription factor hypoxia inducible factor-1α (HIF1α) leading to induction of vascular endothelial growth factor (VEGF) expression. The VEGF signaling cascade results in the activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) release that facilitates key angiogenic events.

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