title: 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.
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Takeshita
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Nagasawa
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000188:drug therapy* / Q000209:etiology; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy*; D015735:Mifepristone / Q000494:pharmacology / Q000627:therapeutic use*; D015434:Panniculitis / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone