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)
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.
Matrix metalloproteinase, glucocorticoid, glucocorticoid receptor, leukocyte, coronary artery disease
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-114324OAI: oai:DiVA.org:liu-114324DiVA: diva2:789272