A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis

Dunn, Louise; Simpson, P.; Prosser, Hamish; Lecce, Laura; Yuen, Gloria; Buckle, Andrew; Sieveking, Daniel; Vanags, Laura Z.; Lim, Patrick; Chow, Renée; Lam, Yuen Ting; Clayton, Zoe; Bao, Shisan; Davies, Michael J.; Stadler, Nadina; Celermajer, David S.; Stocker, Roland; Bursill, Christina A.; Cooke, John P.; Ng, M.

doi:10.2337/db13-0417

Cited by 59 publications

(53 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3 In the vasculature, a knockdown of Txnip was able to restore blood flow and rescue diabetes-related impairment of ischemia-mediated angiogenesis in diabetic mice with surgical introduction of hind limb ischemia. 36 Together, these findings support the important roles of Txnip in multiple organ damage induced by ischemia/reperfusion.…”

Section: Thioredoxin-interacting Protein Exacerbates Ischemia/reperfusupporting

confidence: 59%

The Emerging Role of Thioredoxin-Interacting Protein in Myocardial Ischemia/Reperfusion Injury

Wang

Yoshioka

2016

J Cardiovasc Pharmacol Ther

View full text Add to dashboard Cite

Myocardial ischemia/reperfusion injury represents a major threat to human health and contributes to adverse cardiovascular outcomes worldwide. Despite the identification of numerous molecular mechanisms, understanding of the complex pathophysiology of this clinical syndrome remains incomplete. Thioredoxin-interacting protein (Txnip) has been of great interest in the past decade since it has been reported to be a critical regulator in human diseases with several important cellular functions. Thioredoxin-interacting protein binds to and inhibits thioredoxin, a redox protein that neutralizes reactive oxygen species (ROS), and through its interaction with thioredoxin, Txnip sensitizes cardiomyocytes to ROS-induced apoptosis. Interestingly, evidence from recent studies also suggests that some of the effects of Txnip may be unrelated to changes in thioredoxin activity. These pleiotropic effects of Txnip are mediated by interactions with other signaling molecules, such as nod-like receptor pyrin domain-containing 3 inflammasome and glucose transporter 1. Indeed, Txnip has been implicated in the regulation of inflammatory response and glucose homeostasis during myocardial ischemia/reperfusion injury. This review attempts to make the case that in addition to interacting with thioredoxin, Txnip contributes to some of the pathological consequences of myocardial ischemia and infarction through endogenous signals in multiple molecular mechanisms.

show abstract

Section: Thioredoxin-interacting Protein Exacerbates Ischemia/reperfusupporting

confidence: 59%

The Emerging Role of Thioredoxin-Interacting Protein in Myocardial Ischemia/Reperfusion Injury

Wang

Yoshioka

2016

J Cardiovasc Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…Although both molecular 28 and topological 5 observations indicate that the role of TxnIP in promoting oxidative injury extends beyond its negative regulation of Trx, augmented expression of the protein has been repeatedly associated with the development of diabetes complications. 5,[29][30][31][32] In this study, we found that depletion of EZH2, with either DZNep or shRNA, rendered cultured podocytes vulnerable to the deleterious effects of high-glucose concentrations, leading to an increase in ROS levels and cell death. The augmentation of high glucose-induced oxidative damage in podocytes was, at least in part, mediated by derepression of TxnIP shown by (1) increased podocyte TxnIP mRNA and protein abundance when EZH2-depleted cells were exposed to high-glucose concentrations and (2) abrogation of ROS accumulation by either TxnIP knockdown or Trx overexpression.…”

Section: Discussionmentioning

confidence: 87%

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Siddiqi

Majumder

Thai

et al. 2015

JASN

View full text Add to dashboard Cite

Epigenetic regulation of oxidative stress is emerging as a critical mediator of diabetic nephropathy. In diabetes, oxidative damage occurs when there is an imbalance between reactive oxygen species generation and enzymatic antioxidant repair. Here, we investigated the function of the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) in attenuating oxidative injury in podocytes, focusing on its regulation of the endogenous antioxidant inhibitor thioredoxin interacting protein (TxnIP). Pharmacologic or genetic depletion of EZH2 augmented TxnIP expression and oxidative stress in podocytes cultured under high-glucose conditions. Conversely, EZH2 upregulation through inhibition of its regulatory microRNA, microRNA-101, downregulated TxnIP and attenuated oxidative stress. In diabetic rats, depletion of EZH2 decreased histone 3 lysine 27 trimethylation (H3K27me3), increased glomerular TxnIP expression, induced podocyte injury, and augmented oxidative stress and proteinuria. Chromatin immunoprecipitation sequencing revealed H3K27me3 enrichment at the promoter of the transcription factor Pax6, which was upregulated on EZH2 depletion and bound to the TxnIP promoter, controlling expression of its gene product. In high glucose-exposed podocytes and the kidneys of diabetic rats, the lower EZH2 expression detected coincided with upregulation of Pax6 and TxnIP. Finally, in a gene expression array, TxnIP was among seven of 30,854 genes upregulated by high glucose, EZH2 depletion, and the combination thereof. Thus, EZH2 represses the transcription factor Pax6, which controls expression of the antioxidant inhibitor TxnIP, and in diabetes, downregulation of EZH2 promotes oxidative stress. These findings expand the extent to which epigenetic processes affect the diabetic kidney to include antioxidant repair.

show abstract

“…Previous reports provide compelling evidence that type 2 diabetes impairs arteriogenesis and angiogenesis (4–10). Several observations from the current study, however, suggest this may not be the sole mechanism.…”

Section: Discussionmentioning

confidence: 99%

Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet–Fed Mice

et al. 2016

View full text Add to dashboard Cite

Patients with type 2 diabetes respond poorly to treatments for peripheral arterial disease (PAD) and are more likely to present with the most severe manifestation of the disease, critical limb ischemia. The underlying mechanisms linking type 2 diabetes and the severity of PAD manifestation are not well understood. We sought to test whether diet-induced mitochondrial dysfunction and oxidative stress would increase the susceptibility of the peripheral limb to hindlimb ischemia (HLI). Six weeks of high-fat diet (HFD) in C57BL/6 mice was insufficient to alter skeletal muscle mitochondrial content and respiratory function or the size of ischemic lesion after HLI, despite reducing blood flow. However, 16 weeks of HFD similarly decreased ischemic limb blood flow, but also exacerbated limb tissue necrosis, increased the myopathic lesion size, reduced muscle regeneration, attenuated muscle function, and exacerbated ischemic mitochondrial dysfunction. Mechanistically, mitochondrial-targeted overexpression of catalase prevented the HFD-induced ischemic limb necrosis, myopathy, and mitochondrial dysfunction, despite no improvement in limb blood flow. These findings demonstrate that skeletal muscle mitochondria are a critical pathological link between type 2 diabetes and PAD. Furthermore, therapeutically targeting mitochondria and oxidant burden is an effective strategy to alleviate tissue loss and ischemic myopathy during PAD.

show abstract

A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis

Cited by 59 publications

References 36 publications

The Emerging Role of Thioredoxin-Interacting Protein in Myocardial Ischemia/Reperfusion Injury

The Emerging Role of Thioredoxin-Interacting Protein in Myocardial Ischemia/Reperfusion Injury

The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes

Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet–Fed Mice

Contact Info

Product

Resources

About