liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-114328DOI: 10.3384/diss.diva-114328ISBN: 978-91-7519-149-2 (print)OAI: oai:DiVA.org:liu-114328DiVA: diva2:789291
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
List of papers
1. Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris
Open this publication in new window or tab >>Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris
Show others...
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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68212 (URN)10.1371/journal.pone.0019340 (DOI)000290024700142 ()
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
2. Overexpression of MMP-9 and Its Inhibitors in Blood Mononuclear Cells after Myocardial Infarction - Is It Associated with Depressive Symptomatology?
Open this publication in new window or tab >>Overexpression of MMP-9 and Its Inhibitors in Blood Mononuclear Cells after Myocardial Infarction - Is It Associated with Depressive Symptomatology?
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, e105572- p.Article in journal (Refereed) Published
Abstract [en]

Background: Matrix metalloproteinase (MMP)-9 may play a central role in the development and progression of atherosclerosis. Emerging evidence also indicates an association between MMP-9 and depressive symptomatology. Here, we investigated whether expression of MMP-9 and its inhibitors in blood mononuclear cells and plasma were related to depressive symptoms in patients with a recent myocardial infarction (MI). Methods and Results: Blood sampling was performed between 6 and 18 months after MI in 57 patients. Forty-one clinically healthy subjects were included as controls. Gene expression of MMP-9 and its main tissue inhibitors TIMP-1 and -2 were analyzed in freshly isolated or cultured blood mononuclear cells. Corresponding protein levels were assessed in cell supernatants and plasma. In post-MI patients, mRNA levels of MMP-9 and TIMP-1 and -2 were significantly higher than in controls while protein levels in cell supernatants and plasma did not differ between groups. The Center for Epidemiological Studies - Depression (CES-D) scale was used to assess depressive symptomatology. Repeated assessments during the first 18 months after MI showed significantly higher CES-D scores in patients compared with controls. However, there were no relationships between depressive mood and any of the measurements of MMP-9 or TIMPs. Conclusion: Our findings indicate that overexpression of MMP-9 and TIMPs in blood mononuclear cells and elevated depressive symptoms represent two unrelated phenomena after MI.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110970 (URN)10.1371/journal.pone.0105572 (DOI)000340952200062 ()25153995 (PubMedID)
Note

Funding Agencies|Swedish Research Council [521-2011-3847]; Swedish Heart-Lung Foundation [20120608]

Available from: 2014-10-02 Created: 2014-10-01 Last updated: 2017-12-05
3. The glucocorticoid receptor alpha isoform is overexpressed in blood mononuclear cells from patients with coronary artery disease: Evidence for increased glucocorticoid sensitivity
Open this publication in new window or tab >>The glucocorticoid receptor alpha isoform is overexpressed in blood mononuclear cells from patients with coronary artery disease: Evidence for increased glucocorticoid sensitivity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Context: Coronary artery disease (CAD) is characterized by low-grade chronic inflammation including leukocyte-derived overexpression of matrix metalloproteinase (MMP)-9 and its tissue inhibitors (TIMPs). The mechanisms behind this overexpression are not clarified but may involve dysregulated glucocorticoid regulation of MMP-9.

Objective: We hypothesized that the increased expression of MMP-9 and TIMPs in peripheral blood mononuclear cells (PBMCs) from CAD patients was associated with reduced glucocorticoid sensitivity.

Setting: This was an observational study conducted at the Outpatient Cardiology Clinic at the University Hospital, Linköping, Sweden.

Participants: CAD patients with a history of non-ST-elevation myocardial infarction were consecutively included. Healthy control subjects were randomly recruited from the Swedish Population Register.

Main outcome measures: We measured mRNA and protein levels of glucocorticoid receptors (GR)-α and -β in PBMCs in vivo and further investigated the effects of dexamethasone on MMP-9, TIMP, GR-α and -β expression ex vivo.

Results: The GR-α mRNA levels were markedly increased in PBMCs from CAD patients, whereas GR-β mRNA levels did not differ between patients and controls. Ex vivo, the inhibitory effects of dexamethasone on MMP-9 and TIMP mRNA and protein expression were equal to or slightly higher in patients. Moreover, the dexamethasone treatment resulted in significantly reduced levels of GR-α mRNA in PBMCs.

Conclusion: In contrast to our original hypothesis, we found evidence for increased glucocorticoid sensitivity in PBMCs from CAD patients. It may be suggested that the overexpression of MMP-9 and TIMPs in patients is associated with a state of relative hypocortisolism, thus contributing to a systemic low-grade inflammation.

Keyword
Matrix metalloproteinase, glucocorticoid, glucocorticoid receptor, leukocyte, coronary artery disease
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114324 (URN)
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2015-02-18Bibliographically approved
4. Inflammatory response to acute mental stress is associated with altered cortisol reactivity and telomere shortening in patients with coronary artery disease
Open this publication in new window or tab >>Inflammatory response to acute mental stress is associated with altered cortisol reactivity and telomere shortening in patients with coronary artery disease
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Psychological stress and inflammation are both important risk factors for coronary artery disease (CAD). Susceptibility to mental stress-induced inflammation has been little explored in patients with CAD. Here, we investigated whether stress-induced inflammatory response, more precisely neutrophil activation, was associated with cortisol reactivity, leukocyte telomere length (TL) and carotid atherosclerotic burden in CAD.

Methods: Sixty-four patients with stable CAD underwent a laboratory stress test. Matrix metalloproteinase (MMP)-9, MMP-8, tissue inhibitors (TIMP)-1 and -2, myeloperoxidase (MPO) and salivary cortisol were measured before and 20 min after stress. Leukocyte TL was assessed as well as basal cortisol levels, background psychological factors and atherosclerosis in carotid arteries.

Results: The variation in stress-induced release of neutrophil markers was substantial. Patients were therefore divided into lower and upper tertiles depending on changes in serum MMP-9, T1: -12 %, T3: +27 %, with corresponding changes in MMP-8 and MPO. Clinical or psychological characteristics did not differ between groups, neither did basal levels of neutrophil markers or cortisol. Cardiovascular reactivity during stress was similar in T1 and T3, while cortisol declined after stress only in T3 (-30 %). Leukocyte TL was shorter in T3 than in T1, 0.78 vs 0.88, p = 0.006. Moreover, presence of plaques in right carotid artery differed between T1 and T3, 66 % vs 100 %, p = 0.004.

Conclusion: Stress-induced neutrophil activation in CAD patients was associated with altered cortisol reactivity, leukocyte telomere attrition and increased subclinical atherosclerosis. Data suggest that mental stress testing can identify high-risk patients in need of novel prevention and treatment strategies.

Keyword
Stress, inflammation, matrix metalloproteinase, telomere length, cortisol, coronary artery disease
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114326 (URN)
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2015-02-18Bibliographically approved

Open Access in DiVA

Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity(946 kB)364 downloads
File information
File name FULLTEXT01.pdfFile size 946 kBChecksum SHA-512
a73c3f1cc0cc7b536dd3f8ede153770b91dc933cba432200916f2fff2ff4c59254e132a449a4da9cd99ceb9b9f512d9df39032cb6ad8b32b2eae04ef974ee76a
Type fulltextMimetype application/pdf
omslag(11373 kB)13 downloads
File information
File name COVER01.pdfFile size 11373 kBChecksum SHA-512
68b579ac4816001687ff0c7d706531bd5498a0a62fa34ca8bbf6bebddcff3a81efb85fda50b9714b222ebdd0706c90e75c4a2bd81c21ea51d724fc82ee280698
Type coverMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Jönsson, Simon

Search in DiVA

By author/editor
Jönsson, Simon
By organisation
Division of Cardiovascular MedicineFaculty of Health Sciences
Cardiac and Cardiovascular SystemsImmunology in the medical areaCell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 364 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 782 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf