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Elevated circulating levels of thioredoxin and stress in chronic heart failure
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.ORCID iD: 0000-0001-6353-8041
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2004 (English)In: European Journal of Heart Failure, ISSN 1388-9842, Vol. 6, no 7, 883-890 p.Article in journal (Refereed) Published
Abstract [en]

Background: Chronic heart failure (CHF) is a complex syndrome, in which reactive oxygen species and inflammatory cytokines are important stressors that contribute to the pathogenesis.

Aim: We have studied physiological stress response parameters in CHF, in particular the redox-active regulator thioredoxin.

Subjects: A case–control study was conducted including a consecutive sample of CHF patients (n=27) of NYHA class II and III; comparison control subjects (n=29) were recruited from an association for retired people.

Method: Baseline levels of Trx, lipid peroxides (oxidative stress), TNF and IL-6 cytokines, platelet-activation marker P-selectin, cortisol (as peripheral effector of HPA axis), and the potent antioxidant selenoprotein Trx-reductase were assessed.

Results: Mean (±S.E.M.) plasma levels of Trx were significantly higher in patients with CHF (32±3 ng/ml), than in the healthy subjects (12±3 ng/ml, P<0.0001). Trx levels increased in proportion to severity of disease (NYHA class III>NYHA class II) and degree of stress. Trx elevation correlated well with increased oxidative stress (lipid peroxides, P<0.0001), circulatory P-selectin (P<0.0001), morning level of free salivary cortisol (P=0.0002), and serum creatinine (P=0.0417), but not with pro-inflammatory cytokines TNF and IL-6.

Conclusion: Trx was strikingly elevated in heart failure cases compared with controls, signifying an adaptive stress response that is higher the more severe the disease.

Place, publisher, year, edition, pages
2004. Vol. 6, no 7, 883-890 p.
Keyword [en]
Thioredoxin, Oxidative stress, TNF, IL-6, Inflammation, Chronic heart failure
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14426DOI: 10.1016/j.ejheart.2004.03.003OAI: oai:DiVA.org:liu-14426DiVA: diva2:23484
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-09-22
In thesis
1. Studies on Redox-proteins and Cytokines in inflammation and Cancer
Open this publication in new window or tab >>Studies on Redox-proteins and Cytokines in inflammation and Cancer
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The redox state in the cell plays a major role in determining vital functions and its major imbalance can lead to severe cell injury or death. Redox active proteins and cytokines involved in this process includes thioredoxin (Trx), protein disulfide isomerase (PDI), and tumor necrosis factor (TNF) superfamilies. Trx is a multipotent protein and key regulator of cellular redox balance operating in synergy with Trx reductase and NADPH (the Trx system). Trx has gene regulatory activity of several transcription factors. It also controls in a fascinating way redox-sensitive “on-off” decisions for apoptotic or hypertrophic pathways. Trx protects against H2O2 and TNFmediated cytotoxicity, a pathway in which TNF receptor-binding generates ROS. TNF is an autocrine growth factor and survival factor in vitro and in vivo for B-type of chronic lymphocytic leukemia (B-CLL) cells. The overall aim of this study was to investigate the importance of redox active proteins and cytokines in inflammation and cancer. We focused on: i) the role of Trx, TrxR, and selenium in carcinogenesis and in resistant cancer cells. ii) the importance of Trx in cancer cells and the redox regulation of TNF and its receptors TNFR1 and TNFR2. iii) the potential role of Trx as a key regulator in cellular redox balance, in the pathogenesis of cardiac dysfunction; its relationship to stress response parameters. iv) whether unmutated CLL (UCLL) responses to PKC and ROS pathways were different from mutated CLL (M-CLL) responses.

Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy resistant cells and suggest that redox regulation through the Trx system is an important target for cancer therapy. Trx was strikingly elevated in heart failure cases compared with controls signifying an adaptive stress response that is higher the more severe the disease. TNF autocrine release was redox modulated and the TNF receptors interacted at the cell surface membrane with the redox-active PDI, which excerted a stringent redox-control of the TNFR signaling. The proliferative response as well as increase of autocrine TNF and Trx were higher in U-CLL than in M-CLL.

The overall conclusion of the four papers included in this thesis is that redox-active proteins and cytokines plays an important role in control and regulation of cancer and inflammation. Furthermore, redox regulation via thioredoxin by selenium, may offer novel treatment possibilities for resistant tumors disease.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2007
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 994
Keyword
Thioredoxin (Trx), Selenium, Tumor necrosis factor (TNF), Cancer, nflammation, oxidative stress, Protein-disulfide isomerase (PDI), Tumor necrosis factor receptor (TNFR)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-8798 (URN)978-91-85715-26-8 (ISBN)
Public defence
2007-05-10, Linden, ingång 65, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
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Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-09-22

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Hossain, AkterAlehagen, UrbanDahlström, UlfRosén, Anders

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