Rosuvastatin increases vascular endothelial PPARgamma expression and corrects blood pressure variability in obese dyslipidaemic mice.
OBJECTIVE
Statins improve atherosclerotic diseases through cholesterol-reducing effects. Whether the latter exclusively mediate similar benefits, e.g. on hypertension, in the metabolic syndrome is unclear. We examined the effects of rosuvastatin on the components of this syndrome, as reproduced in mice doubly deficient in LDL receptors and leptin (DKO).


RESULTS
DKO received rosuvastatin (10 mg/kg/day or 20 mg/kg/day) or saline for 12 weeks. Saline-treated DKO mice had elevated blood pressure (BP) and nitric oxide-sensitive BP variability recorded by telemetry. Compared with saline, rosuvastatin (20 mg/kg/day) had no effect on weight gain and a minor effect on plasma cholesterol. Despite incomplete correction of insulin sensitivity, rosuvastatin fully corrected BP and its variability (P = 0.01), in conjunction with upregulation of PPARgamma (but not PPARalpha) in the aortic arch. Rosuvastatin similarly increased PPARgamma (P = 0.002) and SOD1 (P = 0.01) expression in isolated endothelial cells. Both GW9662, a PPARgamma-specific antagonist, and siRNA raised against PPARgamma abrogated rosuvastatin's effect, which was reproduced in PPARgamma- (but not PPARalpha-) dependent transactivation assays.


CONCLUSIONS
Beyond partial improvement in insulin sensitivity, rosuvastatin normalized BP homeostasis in obese dyslipidaemic mice independently of changes in body weight or plasma cholesterol. Upregulation of PPARgamma and SOD1 in the endothelium may be involved as a unique vasculoprotective effect of statin treatment.
Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Belgium.
Fanny
F
Desjardins
Belaïd
B
Sekkali
Wim
W
Verreth
Michel
M
Pelat
Dieuwke
D
De Keyzer
Ann
A
Mertens
Graham
G
Smith
Marie-Christine
MC
Herregods
Paul
P
Holvoet
Jean-Luc
JL
Balligand
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D050171:Dyslipidemias / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D047495:PPAR gamma / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011973:Receptors, LDL; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D011743:Pyrimidines; D011973:Receptors, LDL; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium