on April 28, 2003
Published online before print April 28, 2003, doi: 10.1161/01.CIR.0000065601.83526.3E
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 17, 2002
From the Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain, School of Medicine, Brussels, Belgium. * To whom correspondence should be addressed. E-mail: balligand{at}mint.ucl.ac.be.
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. Methods and 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.
Accepted on February 3, 2003
Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo
Michel Pelat PhD,
Key words: cholesterol • nitric oxide • nervous system, autonomic • blood pressure • rosuvastatin
This article has been cited by other articles:
 |
|
 |
|
  F. Ali, M. Zakkar, K. Karu, E. A. Lidington, S. S. Hamdulay, J. J. Boyle, M. Zloh, A. Bauer, D. O. Haskard, P. C. Evans, et al. Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow J. Biol. Chem., July 10, 2009; 284(28): 18882 - 18892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Gronros, J. Wikstrom, U. Brandt-Eliasson, G. B. Forsberg, M. Behrendt, G. I. Hansson, and L. M. Gan Effects of rosuvastatin on cardiovascular morphology and function in an ApoE-knockout mouse model of atherosclerosis Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2046 - H2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf An Overview of the Extra-Lipid Effects of Rosuvastatin Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 157 - 174. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Desjardins, I. Lobysheva, M. Pelat, B. Gallez, O. Feron, C. Dessy, and J.-L. Balligand Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis Cardiovasc Res, August 1, 2008; 79(3): 527 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Swoap, C. Li, J. Wess, A. D. Parsons, T. D. Williams, and J. M. Overton Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1581 - H1588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Saliez, C. Bouzin, G. Rath, P. Ghisdal, F. Desjardins, R. Rezzani, L.F. Rodella, J. Vriens, B. Nilius, O. Feron, et al. Role of Caveolar Compartmentation in Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation: Ca2+ Signals and Gap Junction Function Are Regulated by Caveolin in Endothelial Cells Circulation, February 26, 2008; 117(8): 1065 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Van den Bergh, A. Vanderper, P. Vangheluwe, F. Desjardins, I. Nevelsteen, W. Verreth, F. Wuytack, P. Holvoet, W. Flameng, J.-L. Balligand, et al. Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness Cardiovasc Res, January 15, 2008; 77(2): 371 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Desjardins, B. Sekkali, W. Verreth, M. Pelat, D. De Keyzer, A. Mertens, G. Smith, M.-C. Herregods, P. Holvoet, and J.-L. Balligand Rosuvastatin increases vascular endothelial PPAR{gamma} expression and corrects blood pressure variability in obese dyslipidaemic mice Eur. Heart J., January 1, 2008; 29(1): 128 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Thireau, B. L. Zhang, D. Poisson, and D. Babuty Heart rate variability in mice: a theoretical and practical guide Exp Physiol, January 1, 2008; 93(1): 83 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.S. Kostapanos, E.N. Liberopoulos, J.A. Goudevenos, D.P. Mikhailidis, and M.S. Elisaf Do statins have an antiarrhythmic activity? Cardiovasc Res, July 1, 2007; 75(1): 10 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Batova, J. DeWever, T. Godfraind, J.-L. Balligand, C. Dessy, and O. Feron The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells Cardiovasc Res, August 1, 2006; 71(3): 478 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang and X.-F. Ming Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin. Med. Res., March 1, 2006; 4(1): 53 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schwartz, S. K. Park, M. S. O'Neill, P. S. Vokonas, D. Sparrow, S. Weiss, and K. Kelsey Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles: Gene-by-Drug-by-Environment Interaction Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1529 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fazan Jr., M. de Oliveira, V. J. Dias da Silva, L. F. Joaquim, N. Montano, A. Porta, M. W. Chapleau, and H. C. Salgado Frequency-dependent baroreflex modulation of blood pressure and heart rate variability in conscious mice Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1968 - H1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lorenz, C. Junger, K. Seidl, A. Gitt, S. Schneider, R. Schiele, H. Wienbergen, R. Winkler, M. Gottwik, W. Delius, et al. Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction? Eur. Heart J., June 1, 2005; 26(11): 1078 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Verreth, D. De Keyzer, M. Pelat, P. Verhamme, J. Ganame, J. K. Bielicki, A. Mertens, R. Quarck, N. Benhabiles, G. Marguerie, et al. Weight Loss-Associated Induction of Peroxisome Proliferator-Activated Receptor-{alpha} and Peroxisome Proliferator-Activated Receptor-{gamma} Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice Circulation, November 16, 2004; 110(20): 3259 - 3269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Massion, C. Dessy, F. Desjardins, M. Pelat, X. Havaux, C. Belge, P. Moulin, Y. Guiot, O. Feron, S. Janssens, et al. Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase (NOS3) Attenuates {beta}-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction Circulation, October 26, 2004; 110(17): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Sonveaux, P. Martinive, J. DeWever, Z. Batova, G. Daneau, M. Pelat, P. Ghisdal, V. Gregoire, C. Dessy, J.-L. Balligand, et al. Caveolin-1 Expression Is Critical for Vascular Endothelial Growth Factor-Induced Ischemic Hindlimb Collateralization and Nitric Oxide-Mediated Angiogenesis Circ. Res., July 23, 2004; 95(2): 154 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Gratton, P. Bernatchez, and W. C. Sessa Caveolae and Caveolins in the Cardiovascular System Circ. Res., June 11, 2004; 94(11): 1408 - 1417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A.M. Plenz, O. Hofnagel, H. Robenek, M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Differential Modulation of Caveolin-1 Expression in Cells of the Vasculature by Statins * Response Circulation, January 20, 2004; 109 (2): e7 - e8. [Full Text] [PDF]
|
|