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The glucocorticoid receptor alpha isoform is overexpressed in blood mononuclear cells from patients with coronary artery disease: Evidence for increased glucocorticoid sensitivity
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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.

Emneord [en]
Matrix metalloproteinase, glucocorticoid, glucocorticoid receptor, leukocyte, coronary artery disease
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-114324OAI: oai:DiVA.org:liu-114324DiVA, id: diva2:789272
Tilgjengelig fra: 2015-02-18 Laget: 2015-02-18 Sist oppdatert: 2018-01-11bibliografisk kontrollert
Inngår i avhandling
1. Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
Åpne denne publikasjonen i ny fane eller vindu >>Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2015. s. 72
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1438
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-114328 (URN)10.3384/diss.diva-114328 (DOI)978-91-7519-149-2 (ISBN)
Disputas
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2015-02-18 Laget: 2015-02-18 Sist oppdatert: 2019-11-15bibliografisk kontrollert

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