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Soluble Fas ligand is associated with natural killer cell dynamics in coronary artery disease
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
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2014 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 233, no 2, 616-622 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Apoptosis of natural killer (NK) cells is increased in patients with coronary artery disease (CAD) and may explain why NK cell levels are altered in these patients. Soluble forms of Fas and Fas ligand (L) are considered as markers of apoptosis. Here, we investigated whether plasma levels of Fas and FasL were associated with NK cell apoptosis and NK cell levels in CAD patients. Methods: Fas and FasL in plasma were determined by ELISA in 2 cohorts of CAD patients; one longitudinal study measuring circulating NK cells and apoptotic NK cells by flow cytometry 1 day, 3 months and 12 months after a coronary event and one cross-sectional study measuring NK cell apoptosis ex vivo. Both studies included matched healthy controls. Fas and FasL were also determined in supernatants from NK cells undergoing cytokine-induced apoptosis in cell culture. Results: In the 12-month longitudinal study, plasma FasL increased by 15% (p less than 0.001) and NK cell levels by 31% (p less than 0.05) while plasma Fas did not change. Plasma FasL and NK cell levels were significantly related at 3 months and 12 months, r = 0.40, p less than 0.01. Furthermore, plasma FasL, but not plasma Fas, correlated with NK cell apoptosis ex vivo in CAD patients, r = 0.54, p less than 0.05. In vitro, cytokine-induced apoptosis of NK cells resulted in abundant release of FasL. Conclusion: In CAD patients, FasL in plasma is associated with both apoptotic susceptibility of NK cells and dynamic changes in circulating NK cells. NK cells are also themselves a potential source of soluble FasL. Our findings link NK cell status to a soluble marker with possible atheroprotective effects thereby supporting a beneficial role of NK cells in CAD.

Place, publisher, year, edition, pages
Elsevier , 2014. Vol. 233, no 2, 616-622 p.
Keyword [en]
Acute coronary syndrome; Coronary artery disease; Immune system; Leukocytes; Natural killer cells; Apoptosis
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-106858DOI: 10.1016/j.atherosclerosis.2014.01.030ISI: 000334337200045OAI: oai:DiVA.org:liu-106858DiVA: diva2:720108
Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2017-12-05
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1467
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:liu:diva-121122 (URN)10.3384/diss.diva-121122 (DOI)978-91-7519-029-7 (ISBN)
Public defence
2015-10-09, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2016-06-14Bibliographically approved

Open Access in DiVA

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