Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/- mice in vivo.
BACKGROUND
Decreased heart rate variability (HRV) and increased blood pressure variability (BPV), determined in part by nitric oxide (NO)-dependent endothelial dysfunction, are correlated with adverse prognosis in cardiovascular diseases. We examined potential alterations in BPV and HRV in genetically dyslipidemic, apolipoprotein (apo) E-/-, and control mice and the effect of chronic statin treatment on these parameters in relation to their NO synthase (NOS)-modifying properties.


RESULTS
BP and HR were recorded in unrestrained, nonanesthetized mice with implanted telemetry devices with or without rosuvastatin. Cardiac and aortic expression of endothelial NOS and caveolin-1 were measured by immunoblotting. Both systolic BP and HR were elevated in apoE-/- mice, with abolition of their circadian cycles. Spectral analysis showed an increase in their systolic BPV in the very-low-frequency (+17%) band and a decrease in HRV in the high-frequency (-57%) band, reflecting neurohumoral and autonomic dysfunction. Decreased sensitivity to acute injection of atropine or an NOS inhibitor indicated basal alterations in both parasympathetic and NOS regulatory systems in apoE-/- mice. Aortic caveolin-1 protein, an inhibitor of endothelial NOS, was also increased in these mice by 2.0-fold and correlated positively with systolic BPV in the very-low-frequency band. Rosuvastatin treatment corrected the hemodynamic and caveolin-1 expression changes despite persisting elevated plasma cholesterol levels.


CONCLUSIONS
Rosuvastatin decreases caveolin-1 expression and promotes NOS function in apoE-/-, dyslipidemic mice in vivo, with concurrent improvements in BPV and HRV. This highlights the beneficial effects of rosuvastatin on cardiovascular function beyond those attributed to lipid lowering.
Pelat
Michel
M
Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain, School of Medicine, Ave Mounier 53, 1200 Brussels, Belgium.
Dessy
Chantal
C
Massion
Paul
P
Desager
Jean-Pierre
JP
Feron
Olivier
O
Balligand
Jean-Luc
JL
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001341:Autonomic Nervous System / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D021081:Chronobiology Disorders / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015716:Electrocardiography, Ambulatory; D005464:Fluorobenzenes / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D016896:Treatment Outcome
D001057:Apolipoproteins E; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse