Abstract
Objective: Mechanisms behind sustained inflammation in patients with coronary artery disease (CAD) are not clarified but hypothalamus-pituitary-adrenal (HPA) axis dysfunction may have a role. Here, we investigated whether inflammatory status of peripheral blood mononuclear cells (PBMCs) was associated with altered glucocorticoid sensitivity in CAD patients.Methods: In 55 CAD patients and 30 controls, mRNA levels of GR-α, GR-β, NF-κB, IκBα, MMP-9 and TIMP-1 were measured in PBMCs. Suppressive effects of dexamethasone on GR-α, GR-β, NF-κB, IκBα, MMP-9 and TIMP-1 mRNA levels were assessed in PBMCs ex vivo. Salivary cortisol was repeatedly measured over 3 days.Results: GR-α mRNA levels were higher in CAD patients than in controls, 0.50 (0.38–0.59) versus 0.26 (0.18–0.37), p < .001, while GR-β mRNA levels were equally low in both groups. GR-α mRNA expression was associated with inflammatory gene expression and, also, with flatter diurnal cortisol rhythm. In both patients and controls, dexamethasone suppressed gene expression of NF-κB, IκBα, MMP-9 and TIMP-1 (p < .001). Dexamethasone also reduced GR-α mRNA levels (p < .001), while LPS increased it (p < .001).Conclusions: PBMCs from CAD patients displayed an inflammatory gene expression profile. This was not explained by reduced glucocorticoid sensitivity. Instead, inflammation was associated with increased expression of GR-α mRNA, suggesting a hypocortisolemic state.Key messages • Peripheral blood mononuclear cells from patients with coronary artery disease (CAD) display an inflammatory gene expression profile. • This inflammatory state cannot be explained by reduced glucocorticoid sensitivity in CAD patients. • Instead, the inflammatory gene expression profile is associated with upregulated levels of glucocorticoid receptor-α mRNA, suggesting a hypocortisolemic state.
Highlights
The presence of inflammation in atherosclerosis is a strong prognostic determinant and a target of therapy [1,2]
The increased gene expression of nuclear factor jB (NF-jB) and IjBa in peripheral blood mononuclear cells (PBMCs) is indicative of a low-grade chronic inflammatory state in coronary artery disease (CAD) patients and may explain why matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinases (TIMP)-1 gene expression is amplified
We investigated if the inflammatory status of PBMCs in CAD patients was associated with HPA axis dysfunction, more precisely reduced glucocorticoid sensitivity
Summary
The presence of inflammation in atherosclerosis is a strong prognostic determinant and a target of therapy [1,2]. Causality has not been fully established, much evidence point towards this enzyme playing an active role in atherosclerosis, from plaque development to plaque destabilization and rupture. It is abundantly expressed in human atherosclerotic lesions, in particular those with unstable morphology [4]. The main inhibitor of MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, is upregulated in PBMCs from patients [7]. Simultaneous overexpression of MMP-9 and TIMP-1 in PBMCs has been described in autoimmune diseases [8,9], likely reflecting a state of sustained and/or dysregulated inflammation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
