Attenuation of cold stress-induced exacerbation of cardiac and adipose tissue pathology and metabolic disorders in a rat model of metabolic syndrome by the glucocorticoid receptor antagonist RU486.
OBJECTIVE
Chronic stress affects the central nervous system as well as endocrine, metabolic and immune systems. However, the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We have now investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology as well as on metabolic parameters in this model.


METHODS
DS/obese rats were exposed to cold stress (immersion in ice-cold water to a depth of 1-2 cm for 2 h per day) with or without subcutaneous injection of the GR antagonist RU486 (2 mg kg(-1)day(-1)) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+)) littermates served as a control.


RESULTS
Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction in DS/obese rats in a manner sensitive to RU486 treatment. Cold stress with or without RU486 did not affect body weight or fat mass. In contrast, cold stress further increased cardiac oxidative stress as well as macrophage infiltration and proinflammatory gene expression in LV and visceral fat tissue, with all of these effects being attenuated by RU486. Cold stress also further increased GR and 11β-hydroxysteroid dehydrogenase type 1 mRNA and protein abundance in LV and visceral adipose tissue, and these effects were again inhibited by RU486. In addition, RU486 ameliorated the stress-induced aggravation of dyslipidemia, glucose intolerance and insulin resistance in DS/obese rats.


CONCLUSIONS
Our results implicate GR signaling in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as of abnormal glucose and lipid metabolism in a rat model of MetS.
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
K
K
Nagasawa
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
N
N
Matsuura
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
Y
Y
Takeshita
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
S
S
Ito
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
Y
Y
Sano
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
Y
Y
Yamada
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
A
A
Uchinaka
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
T
T
Murohara
Department of Pathophysiological Laboratory Sciences, Nagoya, Japan.
K
K
Nagata
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D003080:Cold Temperature; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy; D018149:Glucose Intolerance; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy; D015735:Mifepristone / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D011924:Rats, Zucker; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*
D011965:Receptors, Glucocorticoid; D054411:Receptors, Leptin; D015735:Mifepristone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1