Abstract 1468: Rosuvastatin Increases Vascular Endothelial PPARgamma and Corrects High Blood Pressure in the Absence of Cholesterol Changes in Obese Dyslipidemic Mice
Background- Statins improve atherosclerotic diseases through their cholesterol-reducing effect. Whether the same or other mechanisms mediate a similar benefit in the metabolic syndrome is unclear. We studied the effect of rosuvastatin on the components of this syndrome, as reproduced in mice doubly deficient in LDL receptors and leptin (DKO).
Methods and results- DKO mice (12 weeks old) received rosuvastatin (10 mg/kg/d, s.c;n=6) or saline (n=9) for 12 weeks. Rosuvastatin reduced TG (214±194 vs 467±127 mg/dL), glucose (−30%), insulin (−29.5%) and HOMA (1100±481 vs 2187±703)(all P<0.05) with only minor change in plasma cholesterol (468±323 vs 570±140 mg/dL; n.s.) and no effect on body weight gain. Compared to control (C57Bl6, n=10), DKO mice had elevated systolic (126.7 vs 114.7 mmHg) and diastolic (94.5 vs 85.7 mmHg) blood pressure (BP) and abolition of their circadian rhythm (P<0.05), as recorded with implanted telemetry. Analysis of SBP variability using Fourier transformation showed increased variability in the Very Low Frequency domain (VLF; <0.4Hz; 62.7 vs 54.5 n.u. P<0.001), with blunted sensitivity to the NOS inhibitor L-NAME (−61%; P<0.05), indicative of altered NO-dependent BP control. Compared with placebo, rosuvastatin corrected all parameters, i.e. lowered SBP (113.2 mmHg) and DBP (90.9 mmHg) (all P<0.05), and restored circadian and short-term variability. As we had observed similar changes in DKO after diet-induced weight loss, we examined the effect of rosuvastatin on the expression of selected genes regulated by diet restriction on the basis of a high-density transcriptomic analysis. PPARγ was found to be similarly upregulated by diet restriction and rosuvastatin in the aortic wall (+100 %; n=6; P<0.05). Importantly, rosuvastatin directly upregulated PPARγ and downstream SOD1 mRNA (+47% and +52%; both P<0.05, n=5– 6; by RT-qPCR) in cultured aortic endothelial cells.
Conclusion- As with diet restriction, rosuvastatin improved insulin sensitivity and BP regulation in DKO, but without effect on body weight loss or major change in plasma cholesterol. The increase in PPARγ and SOD1 (an anti-oxidant, PPAR-responsive gene) in endothelial cells may represent a unique mechanism of vascular protection and BP correction by statin treatment.