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European Heart Journal Advance Access published online on December 6, 2007
European Heart Journal, doi:10.1093/eurheartj/ehm540
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

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

Fanny Desjardins1, Belaïd Sekkali1, Wim Verreth2, Michel Pelat1, Dieuwke De Keyzer2, Ann Mertens2, Graham Smith3, Marie-Christine Herregods4, Paul Holvoet2 and Jean-Luc Balligand1,*

1 Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Belgium
2 Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit, Leuven, Belgium
3 AstraZeneca, Macclesfield, Cheshire, UK
4 Division of Cardiology, Katholieke Universiteit, Leuven, Belgium

Received 3 November 2006; revised 22 October 2007; accepted 29 October 2007.

* Corresponding author: UCL-FATH 5349, Vésale+5, 52 Avenue Mounier, 1200 Brussels, Belgium. Tel: +32 2 764 5268, Fax: +32 2 762 5269. Email: balligand{at}mint.ucl.ac.be

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.

Key Words: Statin • Blood pressure • Nitric oxide • Superoxide dismutase • PPAR{gamma}

This paper was guest edited by Dr Nikolaus Marx, Department of Internal Medicine II-Cardiology, University of Ulm, Germany


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[Abstract] [PDF]


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