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

Yuuri Takeshita, Shogo Watanabe, Takuya Hattori, Kai Nagasawa, Natsumi Matsuura, Keiji Takahashi, Toyoaki Murohara, Kohzo Nagata

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)741-750
Number of pages10
JournalHypertension Research
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 1 2015
Externally publishedYes

Keywords

  • adipose tissue
  • cardiac remodeling
  • glucocorticoid receptor
  • glucose metabolism
  • metabolic syndrome

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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