Blockade of glucocorticoid receptors with RU486 attenuates cardiac damage and adipose tissue inflammation in a rat model of metabolic syndrome

Abstract

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11β-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome

“…DS/ obese rats die after 15 week of age and their survival rate at 18 weeks was approximately 35% (Hattori et al 2011). From 9 to 13 week, DS/obese rats present progressive hypertension, LV diastolic dysfunction, LV hypertrophy, fibrosis, and insulin resistance Takeshita et al 2015). Also, hyperphagia is gradually reduced after 11 weeks.…”

Glucocorticoids and programming of the microenvironment in heart

“…Recently, it has been demonstrated that GR-knockout monocyte-derived macrophages increase pro-inflammatory chemokine CCL5 and decreases interleukin 1α (IL-1α), a cytokine that plays a central role in delaying myofibroblast differentiation during the inflammatory phase of healing after ischemic myocardial injury (Galuppo et al 2017). Blockade of GR inhibited macrophage infiltration and gene expression of monocyte chemoattractant protein-1, osteopontin, cyclooxygenase-2 and tumor necrosis factor-α (TNFα) in the left ventricular myocardium, contributing to attenuation of cardiac injury in rats with metabolic syndrome (Takeshita et al 2015). It is known that IL-10 is a crucial GR target gene in macrophages.…”

Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure

“…For insulin tolerance tests (ITTs), mice fasted for 5 h were injected intraperitoneally with 1 IU/kg insulin (Actrapid Penfill; Novo Nordisk, Paris, France). Whole-tail vein blood was collected at baseline (t 0 ) and 15 min (t 15 ), and centrifuged plasma samples were stored at 280°C. For both tests, blood glucose was measured at the tail vein using an automatic Accu-Chek Performa glucometer (Roche, Meylan, France) at indicated times.…”

“…Furthermore, in vivo MR pharmacological blockade by eplerenone reduces the expression of proinflammatory factors in genetically obese and diabetic mice, suggesting a role for MR as a key factor mediating obesity-related inflammation and insulin resistance (14). The implication of GR in the pathophysiology of metabolic syndrome has been suggested by the pharmacological blockade of GR (by RU486), which improved fasting hyperinsulinemia, insulin resistance, and glucose intolerance (15). More recently, the role of the adipocyte GR was investigated in vivo using constitutive murine models of adipocyte GR deletion (16)(17)(18)(19)(20).…”