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NK cell apoptosis in coronary artery disease. Relation to oxidative stress
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
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2008 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, no 1, 65-72 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Natural killer (NK) cells, key elements in initiation and modulation of immune responses, were recently found to be reduced in coronary artery disease (CAD). To clarify mechanisms behind this reduction, we here investigated NK cell apoptosis in CAD patients. Since oxidative stress has been linked to NK cell apoptosis, we related the findings to oxidative stress in vivo and evaluated the ex vivo susceptibility of NK cells to oxidized lipids. Methods and results: The number of apoptotic NK cells in peripheral blood was significantly increased in CAD patients compared to controls. Purified NK cells from CAD patients also showed a higher rate of spontaneous apoptosis ex vivo. Dose- and time-dependent effects of oxidized LDL and 7β-hydroxycholesterol (7βOH) on apoptosis and ROS production were determined in NK cells from blood donors. Thereafter, purified NK cells from CAD patients and healthy controls were exposed to the oxidized lipids in a paired design. NK cells from patients were more susceptible to apoptosis induced by oxidized LDL, in particular 7βOH, compared to cells from controls. Plasma measurements of LDL protein oxidation and lipid peroxidation did not show any differences between patients and controls. On the other hand, plasma carotenoids were significantly decreased in patients and inversely correlated to NK cell apoptosis rate. Conclusion: The rate of spontaneous NK cell apoptosis was increased in CAD patients. Although NK cells in CAD patients were more sensitive to oxidized lipids ex vivo, indicating a mechanism contributing to the reduced NK cell activity in CAD, the data could not verify an obvious link between NK cell apoptosis and increased oxidative stress in vivo. © 2007 Elsevier Ireland Ltd. All rights reserved.

Place, publisher, year, edition, pages
2008. Vol. 199, no 1, 65-72 p.
Keyword [en]
Aged Apoptosis/*immunology Carotenoids/blood Cells, Cultured Coronary Artery Disease/*immunology/*metabolism/pathology Female Humans Killer Cells, Natural/*metabolism/*pathology Lipid Peroxidation/immunology Lipoproteins, LDL/blood Male Middle Aged Necros
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-43384DOI: 10.1016/j.atherosclerosis.2007.10.031Local ID: 73685OAI: diva2:264243
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2015-09-08Bibliographically approved
In thesis
1. Detection of apoptosis in patients with coronary artery disease: Assessment of temporal patterns and potential sources
Open this publication in new window or tab >>Detection of apoptosis in patients with coronary artery disease: Assessment of temporal patterns and potential sources
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The atherosclerotic process and its consequences are considered driven by an imbalance between pro- and ant-inflammatory actions. One contributing factor in this scenario is an altered regulation of apoptosis, which affects both immune, vascular and myocardial cells. The general aim of this thesis was to measure soluble markers of apoptosis in peripheral venous blood, in various clinical stages of coronary artery disease (CAD) and to further identify possible sources with specific focus on natural killer (NK) cell apoptosis and myocardial ischemia-reperfusion (IR)-injury.

There was evidence of an increased apoptosis of NK cells, but not T cells, in the circulation of CAD patients. Spontaneous NK cell apoptosis and the cells´ sensitivity to oxidative stress in the form of oxidized lipids ex vivo, were increased. Findings were thus suggestive of an enhanced apoptosis contributing to the reduced NK cell activity seen in CAD. However, we could not verify that oxidative stress in the circulation was a driving force behind this loss.

Soluble forms of the cell surface bound receptors of apoptosis include soluble (s) Fas and sFas ligand (L). They are detected in plasma and used as surrogate markers of apoptosis. Here we investigated the relationship between these markers and NK cell apoptosis and NK cell levels, in a 12 month longitudinal study on CAD patients. Plasma levels of sFasL correlated with increased susceptibility to NK cell apoptosis ex vivo but also with the levels of NK cells in the circulation after a coronary event. NK cells undergoing apoptosis ex vivo were also found to be a major source of sFasL themselves, indicating potential usefulness of sFasL in monitoring changes in NK cell levels.

Apoptosis is suggested to be a key event in IR-injury, resulting in increased infarct size, left ventricular (LV) dysfunction, remodeling and heart failure. We investigated soluble markers of apoptosis in relation to these parameters in a ST-elevation myocardial infarction (STEMI) population. In addition to sFas and sFasL, we also measured tumor necrosis factor (TNF) receptor (R) I and II in this study. Acute phase levels of sTNFRI and sTNFRII, but not sFas or sFasL, correlated to cardiac MR (CMR) measures of infarct size and LV-dysfunction at 4 months after the ischemic event. Also, the soluble markers of apoptosis were correlated with matrix metalloproteinase (MMP)-2, a mechanistic trigger for cardiomyocyte apoptosis, further strengthening the role of apoptosis in IR-injury.

Finally we explored the temporal patterns of soluble markers of apoptosis after an MI and, furthermore, investigated possible differences between patients presenting with a non(N)-STEMI versus STEMI. The sTNFRI/II and the sFas/sFasL pathways of apoptosis showed different temporal changes indicating diverse roles of these two systems. NSTEMI and STEMI patients however, shared these temporal patterns pointing to apoptosis as equally involved in either infarct type. Furthermore sTNFRs, but not sFas/sFasL correlated to levels of cytokine interleukin (IL)-6 illustrating the overlapping role TNF signaling in inflammation and apoptosis, while again suggesting differences between the TNF and the Fas/FasL systems during myocardial IR--‐injury.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 89 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1467
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
urn:nbn:se:liu:diva-121122 (URN)10.3384/diss.diva-121122 (DOI)978-91-7519-029-7 (print) (ISBN)
Public defence
2015-10-09, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2015-09-08Bibliographically approved

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Li, WeiLidebjer, CarolineYuan, XimingSzymanowski, AleksanderBackteman, KarinErnerudh, JanLeanderson, PerNilsson, LennartSwahn, EvaJonasson, Lena
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