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Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
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2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 4Article in journal (Refereed) Published
Abstract [en]

Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p andlt; 0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p andlt; 0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p andlt; 0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD-a phenomenon that may have clinical implications in the course of disease.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2011. Vol. 6, no 4
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68212DOI: 10.1371/journal.pone.0019340ISI: 000290024700142OAI: oai:DiVA.org:liu-68212DiVA: diva2:416879
Note
Original Publication: Simon Jönsson, Anna Lundberg, Hanna Kälvegren, Ida Bergström, Aleksander Szymanowski and Lena Jonasson, Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris, 2011, PLOS ONE, (6), 4. http://dx.doi.org/10.1371/journal.pone.0019340 Licensee: Public Library of Science (PLoS) http://www.plos.org/Available from: 2011-05-13 Created: 2011-05-13 Last updated: 2015-02-18
In thesis
1. Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
Open this publication in new window or tab >>Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammation is closely associated with development of atherosclerosis. The proteolytic enzyme matrix metalloproteinase (MMP)-9 is considered to play a prominent role in this process. MMP-9 has also been introduced as a marker for plaque vulnerability. Still, the possible mechanisms behind altered levels of MMP-9 and its tissue inhibitors (TIMPs) in patients with atherosclerotic disease remain unclear. The general aim of this thesis was to compare leukocyte-derived MMP-9 and TIMPs in patients with coronary artery disease (CAD) and healthy controls and to further relate the findings to psychological stress and glucocorticoid sensitivity.

Levels of leukocyte-derived MMP-9 and TIMP-1 showed a significant difference between CAD patients and controls. Neutrophils in CAD patients were more prone to release MMP-9 and furthermore, PBMCs in patients expressed higher levels of MMP-9 and TIMP-1 and -2 mRNA than PBMCs in controls while there were no differences in plasma or serum levels. The increase in leukocyte-derived levels of MMP-9 and TIMPs indicate the presence of preactivated leukocytes in CAD.

Inflammation has been proposed as a mechanistic link between cardiovascular risk and depressive symptoms. We investigated whether the overexpression of leukocyte-derived MMP-9 and TIMPs in CAD patients was associated with psychological factors. Patients exhibited sustained elevations in depressive symptoms, however, these symptoms were not related to any MMP-9 or TIMP variables. The findings suggest that overexpression of leukocyte-derived MMP-9 and TIMPs and elevated depressive scores represent two parallel phenomena in CAD.

Chronic inflammation may be associated with reduced glucocorticoid sensitivity. We found that PBMCs in CAD patient expressed significantly increased levels of glucocorticoid receptor (GR)-α mRNA, whereas GR-β mRNA levels did not differ between patients and controls. Moreover, in ex vivo assays, dexamethasone efficiently suppressed MMP-9 and TIMPs equally or even more in patients compared to controls. The findings provide evidence for enhanced glucocorticoid sensitivity in CAD patients and also suggest that a state of relative hypocortisolism may contribute to the overexpression of leukocyte-derived MMP-9 and TIMPs.

Lastly, we explored the release of MMP-9, TIMPs and cortisol in response to acute mental stress in CAD patients. Patients who exhibited a significant stress-induced increase in serum MMP-9 also exhibited an altered cortisol response. Moreover, the susceptibility to stressinduced increase in serum MMP-9 was associated with shorter leukocyte telomere length and atherosclerotic plaque burden. The findings highlight the existence of a high-risk group which may be in need of improved diagnostic and therapeutic strategies.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1438
National Category
Cardiac and Cardiovascular Systems Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114328 (URN)10.3384/diss.diva-114328 (DOI)978-91-7519-149-2 (print) (ISBN)
Public defence
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2015-02-18Bibliographically approved

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Jönsson, SimonKälvegren, HannaBergström, IdaSzymanowski, AleksanderJonasson, Lena
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