Role of glucocorticoid receptor expression in Chronic Chagas Cardiomyopathy: implications for inflammation and cardiac hypertrophy

Abstract

Introduction: Chronic Chagasic Cardiomyopathy (CCC) has an infectious and inflammatory nature. Recent data also suggest an association with altered regulation of glucocorticoid (GC)-mediated circuits failing to control systemic inflammation. However, the involvement of glucocorticoid receptors (GR) and their isoforms have been unexplored.

Materials and methods: The expression of GR-α/β isoforms, 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), inflammatory cytokines, and the GC-regulated gene tristetraprolin (TTP) in peripheral blood mononuclear cells (PBMCs) as well as GR immunoreactivity in the myocardium from CCC individuals were evaluated by qPCR and immunohistochemistry respectively. Heart control samples with no evidence of structural heart disease and from ischemic cardiomyopathy patients were included. The presence of inflammatory infiltrates and fibrosis were also recorded.

Results: GR-α was expressed similarly in the PBMCs from Co and CCC individuals, but 11β-HSD1 expression was increased only in CCC, conjointly with enhanced ratios of IL-6/TTP and IFN-γ/TTP. In the inflamed myocardium from CCC patients, positive GR expression correlated with the intensity of the inflammatory infiltrate and cardiac hypertrophy.

Conclusion: The infectious and inflammatory nature of CCC pathology seems strongly connected with the expression of GR in cardiac tissue samples, providing a stimulating background for further studies addressed to elucidate the influence of GR expression and function on CCC pathophysiology and cardiomyocyte hypertrophy.

Keywords: 11β-hydroxysteroid dehydrogenase type 1; cardiomyocyte; chronic chagasic cardiomyopathy; glucocorticoid receptor; hypertrophy; ischemic cardiomyopathy.

Figure 1

Plasma levels of HPA-axis-related factors in Co, CCC, and ICM patients. (A) Cortisol, (B) DHEA-S, and (C) Cortisol/DHEA-S ratio. Lines represent means ± SEM. *p<0.05; **p<0.01.

Figure 2

Expression of immuno-endocrine-related genes in peripheral blood mononuclear cells. (A) Glucocorticoid receptor-α (GR-α). (B) 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1). (C) Tristetraprolin (TTP). (D) IL-6. (E) IL-1β. (F) IFN-γ. (G) TNF-α. (H) IL-6/TTP ratio. (I) IL-1β/TTP ratio. (J) IFN-γ/TTP ratio. (K) TNF-α/TTP ratio. The results are expressed as arbitrary units (AU). Lines represent means ± SEM. *p<0.05; **p<0.01; ***p<0.001.

Figure 3

Glucocorticoid receptor expression in human cardiac tissue samples. (A) Representative images of hematoxylin/eosin staining from the interventricular septum in Co, CCC, and ICM individuals (O.M 400X). A diffuse inflammatory infiltrate is observed in CCC patients (middle panel, white arrows). Inserts show fibrosis for each group. (B) Percentage of GR+ inflammatory cells in 10 HPF (O.M 400X). (C) Fibrosis as a percentage of the total area. (D) GR localization and immunoreactivity. GR+ cells (brown) are mainly nuclear (white arrows); yellow arrows indicate GR-negative cells (light blue). (E) GR+ expression in cardiomyocytes, quantified in 10 HPF (O.M 400X). (F) GR+ expression in CCC patients, categorized by LVEDD. (G) Cardiomyocyte diameters (right panel) and comparison by GR expression (left panel). (H) Cardiomyocyte nuclear areas (right panel) and comparison by GR expression (left panel). Data are means ± SEM. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. HPF, high power field; O.M., original magnification.

Figure 4

Conceptual graph showing the association between endocrine dysregulation, inflammation, GR expression and CCC pathology. Immune-endocrine imbalances and parasite persistence may favor the establishment of a chronic proinflammatory state in parallel with cardiac inflammation. Cardiomyocytes might upregulate GR expression to counter inflammation which could favor the development of hypertrophy. At the same time fibrosis would develop in response to tissue damage due to inflammation. .