Rosuvastatin increases vascular endothelial PPAR gamma expression and corrects blood pressure variability in obese dyslipidaemic mice

Aims 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). Methods and 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 PPAR gamma (but not PPAR alpha) in the aortic arch. Rosuvastatin similarly increased PPAR gamma (P = 0.002) and SOD1 (P = 0.01) expression in isolated endothelial cells. Both GW9662, a PPAR gamma-specific antagonist, and siRNA raised against PPAR gamma abrogated rosuvastatin's effect, which was reproduced in PPAR gamma- (but not PPAR alpha-) dependent transactivation assays. Conclusion 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 PPAR gamma and SOD1 in the endothelium may be involved as a unique vasculoprotective effect of statin treatment.