Cardiovascular Drugs and Therapy

, Volume 28, Issue 4, pp 347–360 | Cite as

Thioredoxin-Interacting Protein: Pathophysiology and Emerging Pharmacotherapeutics in Cardiovascular Disease and Diabetes

  • Cher-Rin Chong
  • Wai Ping A. Chan
  • Thanh H. Nguyen
  • Saifei Liu
  • Nathan E. K. Procter
  • Doan T. Ngo
  • Aaron L. Sverdlov
  • Yuliy Y. Chirkov
  • John D. Horowitz


The thioredoxin system, which consists of thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), has emerged as a major anti-oxidant involved in the maintenance of cellular physiology and survival. Dysregulation in this system has been associated with metabolic, cardiovascular, and malignant disorders. Thioredoxin-interacting protein (TXNIP), also known as vitamin D-upregulated protein or thioredoxin-binding-protein-2, functions as a physiological inhibitor of Trx, and pathological suppression of Trx by TXNIP has been demonstrated in diabetes and cardiovascular diseases. Furthermore, TXNIP effects are partially Trx-independent; these include direct activation of inflammation and inhibition of glucose uptake. Many of the effects of TXNIP are initiated by its dissociation from intra-nuclear binding with Trx or other SH-containing proteins: these effects include its migration to cytoplasm, modulating stress responses in mitochondria and endoplasmic reticulum, and also potentially activating apoptotic pathways. TXNIP also interacts with the nitric oxide (NO) signaling system, with apparent suppression of NO effect. TXNIP production is modulated by redox stress, glucose levels, hypoxia and several inflammatory activators. In recent studies, it has been shown that therapeutic agents including insulin, metformin, angiotensin converting enzyme inhibitors and calcium channel blockers reduce TXNIP expression, although it is uncertain to what extent TXNIP suppression contributes to their clinical efficacy. This review addresses the role of TXNIP in health and in cardiovascular and metabolic disorders. Finally, the potential advantages (and disadvantages) of pharmacological suppression of TXNIP in cardiovascular disease and diabetes are summarized


Thioredoxin-interacting protein Thioredoxin Diabetes Cardiovascular diseases Oxidative stress Inflammation Nitric oxide Therapeutics 



This work was supported in part by grants from the National Health and Medical Research Council (NHMRC) of Australia and the Queen Elizabeth Hospital Research Foundation to JDH. CRC is a recipient of NHMRC postgraduate scholarship; SL and NEKP are recipients of University of Adelaide postgraduate scholarships. The authors have no other relevant conflict of interest to disclose.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cher-Rin Chong
    • 1
  • Wai Ping A. Chan
    • 1
  • Thanh H. Nguyen
    • 1
  • Saifei Liu
    • 1
  • Nathan E. K. Procter
    • 1
  • Doan T. Ngo
    • 1
  • Aaron L. Sverdlov
    • 1
  • Yuliy Y. Chirkov
    • 1
  • John D. Horowitz
    • 1
    • 2
  1. 1.Cardiology and Clinical Pharmacology Department, Basil Hetzel InstituteQueen Elizabeth Hospital, University of AdelaideAdelaideAustralia
  2. 2.Cardiology DepartmentQueen Elizabeth HospitalWoodvilleSouth Australia

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