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(Circulation. 2003;107:2480.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide–Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E^-/- Mice In Vivo

Michel Pelat, PhD; Chantal Dessy, PhD; Paul Massion, MD; Jean-Pierre Desager, PhD; Olivier Feron, PhD; Jean-Luc Balligand, MD, PhD

From the Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain, School of Medicine, Brussels, Belgium.

Correspondence to Dr Jean-Luc Balligand, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, University of Louvain, School of Medicine, Ave Mounier 53, 1200 Brussels, Belgium. E-mail balligand{at}mint.ucl.ac.be

	Abstract

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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.

Key Words: cholesterol • nitric oxide • nervous system, autonomic • blood pressure • rosuvastatin

	Introduction

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Hypercholesterolemia, a well-known risk factor for cardiovascular diseases, is associated with disorders of the short-term and long-term regulation of blood pressure (BP)¹ and heart rate (HR)² that may precipitate cardiovascular events.³ Indeed, an increase in BP variability and, conversely, a decrease in HR variability both are predictive of increased cardiovascular morbidity and mortality.⁴ In particular, several studies emphasized the negative prognostic value of enhanced BP variability toward end-organ damage, even independently of average BP levels.^4,5

The activity of the parasympathetic and sympathetic nervous systems is the main determinant of BP and HR homeostasis through its modulation of the arterial baroreflex. In addition, recent work identified the role of vascular nitric oxide (NO) as a second short-term buffering mechanism in response to increases in arterial BP.⁶ Accordingly, mice with a genetic deletion of the endothelial NO synthase, or eNOS, have both elevated average BP levels^7,8 and increased BP variability,^9,10 as observed in other animal models after pharmacological NOS blockade.⁹ Numerous studies have demonstrated that hypercholesterolemia is associated with defects of the NO-dependent endothelial function, including in genetically dyslipidemic, apolipoprotein (apo) E–deficient mice.¹¹ The correlation between NOS function and HR or BP variability in this mouse strain, to the best of our knowledge, has never been examined.

We therefore studied BP and HR variabilities, as well as their modulation by NOS and the autonomic nervous system, in hyperlipidemic, apoE^-/- mice by telemetry. These measurements were correlated with the expression, in cardiac and aortic tissues, of caveolin-1, a structural protein of caveolae, that acts as an allosteric inhibitor of eNOS, thereby reducing its ability to produce NO.^12,13 Finally, we studied the effect of a chronic treatment with the HMG-CoA inhibitor rosuvastatin on these parameters.

	Methods

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Animals and Telemetric Recordings
Male apoE-deficient and control mice of the same genetic background (C57Bl/6; 6 to 8 weeks old; Charles River UK, Ltd, Margate, UK) were treated with rosuvastatin (supplied by AstraZeneca UK; 80 mg · kg^-1 · d^-1 PO) or placebo for 2 weeks. The dose of rosuvastatin was chosen according to preliminary lipid-lowering experiments in apoE^-/- mice and to maximize the potential for peripheral (as opposed to hepatic) pharmacodynamic effects. Animals were kept on a 12-hour light/dark cycle. BP signals (and HR, derived from pressure waves) from the aortic arch were measured in conscious, unrestrained animals with surgically implanted, miniaturized telemetry devices (Datascience Corp). After 2 weeks of recovery, short- or long-term (24 hours) online recordings were digitized (range, 20 to 2000 Hz) and stored for further analysis. Measurements were repeated after rosuvastatin treatment (or placebo) in the same mice.

In all mice, the acute effects of atropine (1 mg/kg) and of a nonselective NOS inhibitor (N^G-nitro-L-arginine methyl ester, or L-NAME; Sigma; 30 mg/kg) were tested after intraperitoneal injection and subsequent recording for 15 minutes.

All animal procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

Spectral Analysis of HR and BP Variabilities
Spectral analysis using a fast Fourier transformation algorithm on sequences of 512 points was performed by use of the HEM 3.4 software (Notocord Systems) on BP and HR recordings. The area under the curve was calculated for the very-low-frequency (VLF: 0.05 to 0.4 Hz), low-frequency (LF: 0.4 to 1.5 Hz), and high-frequency (HF: 1.5 to 5.0 Hz) bands, as previously defined in the mouse species.^10,14 Spectral variability at each bandwidth was normalized to the total spectral area.

Immunoblotting Experiments
Equal amounts of cardiac and aortic protein extracts were processed for Western blot analysis as described by Feron et al^12,15 with monoclonal anti-eNOS and anti–caveolin-1 antibodies (Becton-Dickinson). Densitometric signals were normalized by the immunoblotted signal for the chaperone protein hsp90 on the same filter. We previously verified that treatment with a statin has no effect on hsp90 expression in cultured cells¹⁶ or in tissue extracts with rosuvastatin in the present study. Normalized results are expressed as percentage of mean densitometric values of control (C57Bl/6) tissues on the same blot.

Statistical Analysis
All results are expressed as mean±SEM. All statistical comparisons were performed by use of Student’s t test or 1-way ANOVA where appropriate. A probability value of P<0.05 was considered significant.

	Results

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ApoE^-/- Mice Have Increased BP and HR With Loss of Circadian Cycles: Restoration by Rosuvastatin
In control (C57Bl/6) mice, continuous (24 hours) BP and HR recordings revealed a typical variation during the light-dark cycle, ie, light (corresponding to a resting period in mice) values of systolic BP (SBP), diastolic BP (DBP), and HR were significantly lower than dark (activity period for mice) values. By contrast, circadian variations of HR, SBP, and DBP were totally abolished in untreated apoE^-/- mice (Figure 1, A, C, and E, and Table). ApoE^-/- mice also had higher mean 24-hour SBP (137.4±0.9 versus 113.7 mm Hg, P<0.05) and DBP (100.0±0.7 versus 89.0±0.7 mm Hg, P<0.05) values and higher mean HR compared with controls (509.9±3.0 versus 440.3±5.4 bpm, P<0.05).

View larger version (29K): [in this window] [in a new window]   Figure 1. Circadian variations of BP and HR in apoE-/- and C57Bl/6 control mice. Time course of SBP (A and B), DBP (C and D), and HR (E and F) over 24 hours obtained before (A, C, and E) and after (B, D, and F) treatment for 2 weeks with 80 mg · kg-1 · d-1 rosuvastatin, in C57Bl/6 (solid squares) (n=6 to 8) and apoE-/- mice (open circles) (n=6 to 8). Thick dark lines represent dark cycles. Mean values (±SEM) of SBP, DBP, and HR were calculated for each 60-minute sequence of recording.

View this table: [in this window] [in a new window]   Day and Night Values of HR and SBP and DBP in C57BL/6 (Control) and ApoE-Deficient Mice

Two weeks of treatment with rosuvastatin had no significant effect on HR, SBP, or DBP values in control mice but reduced all parameters in apoE^-/- mice to control levels (412±5.6 bpm, 104.1±1.4 mm Hg, and 77.2±1.0 mm Hg, respectively). Figure 1, B, D, and F, shows that rosuvastatin also restored the circadian variations of these parameters in apoE^-/- mice.

ApoE^-/- Mice Have Altered Parasympathetic Control of HR That Is Corrected by Rosuvastatin
Spectral analysis of SBP and HR signals in the frequency domain revealed that SBP and HR variabilities of apoE^-/- mice were increased in the VLF band (see Methods and Figure 2, A and B), indicating general alterations of neurohumoral control. More specifically, Figure 2C shows that apoE^-/- mice had decreased HR variability in the HF band, revealing defects in their parasympathetic control.

View larger version (11K): [in this window] [in a new window]   Figure 2. Spectral analysis of SBP variability and HR variability in apoE-/- and control mice with or without rosuvastatin treatment. After normalization to whole power spectra, area under curve for variability of SBP and HR was calculated for each apoE-/- or control mouse, in absence (apoE -/-: open columns, n=6 to 8; controls: black columns, n=6 to 8) or in presence (apoE R, hatched columns; and C57 R, gray columns) of rosuvastatin treatment. Results are illustrated for specific frequency bands, ie, VLF (0.05 to 0.4 Hz) of SBP (A) or HR (B), reflecting neurohumoral influences, and HF (1.5 to 5 Hz) of HR (C), reflecting parasympathetic control. *P<0.05 vs C57Bl/6 without treatment, # P<0.05 vs apoE-/- without treatment.

Treatment with rosuvastatin had no influence on these parameters in control mice. In apoE^-/- mice, rosuvastatin normalized SBP and HR variabilities in the VLF band, as well as HR variability in the HF band (Figure 2C, hatched bars).

ApoE^-/- Mice Have Impaired Sensitivity to Atropine and NOS Inhibition That Is Restored by Rosuvastatin
The integrity of the vagal efferent and of the NOS pathways, 2 main determinants of HR and SBP variabilities, was assessed in all groups of animals by acute challenge with either the muscarinic cholinergic antagonist atropine or the NOS inhibitor L-NAME under telemetric monitoring in the awake state.

The effects of atropine on absolute HR and HR variability are shown in Figure 3. In C57Bl/6 mice, atropine dramatically increased HR (Figure 3A) but reduced HR variability in the HF and LF bands (Figure 3B) and decreased HR variance (Figure 3C), as expected. In apoE^-/- mice, atropine induced much smaller changes in absolute HR (Figure 3A) and HR variance (Figure 3C). Of note, rosuvastatin (which had no effect in control animals) improved HR variance (Figure 3C, hatched bars) and restored HR response (Figure 3A, hatched bars) to atropine in apoE^-/- mice.

View larger version (27K): [in this window] [in a new window]   Figure 3. Differential sensitivity of apoE-/- and control mice to atropine: influence of rosuvastatin treatment. A, Effect of atropine (1 mg/kg IP) on HR is compared in apoE-/- and C57Bl/6 mice with (C57 R, gray bars; apoE R, hatched bars) or without (C57, black bars; apoE, white bars) rosuvastatin treatment (n=6 in each group). Tachycardic effect of atropine is selectively lost in apoE-/- mice and restored to control levels after 2 weeks of treatment with rosuvastatin. P<0.05 vs baseline in *C57, $C57 R, and #apoE R. B, Representative power spectra of HR variability (HRV) before and after atropine administration in a C57Bl/6 mouse. Note decrease in HRV across whole HF band after atropine (bold tracing), reflecting loss of parasympathetic control of HR. C, Absolute changes in HRV induced by atropine in apoE-/- and control mice, with or without rosuvastatin treatment (same labels as in A). *P<0.05 vs C57, C57 R, and apoE R.

The effects of acute NOS inhibition are shown in Figure 4. In control C57Bl/6 mice, NOS inhibition resulted in an increase in SBP (Figure 4A) and an increase in SBP variability in the VLF band (Figure 4, B and C), as expected. In apoE^-/- mice, NOS inhibition produced much smaller changes in SBP (Figure 4A) and SBP variability in the VLF band (Figure 4C).

View larger version (22K): [in this window] [in a new window]   Figure 4. Differential sensitivity of apoE-/- and control mice to L-NAME: influence of rosuvastatin treatment. A, Effect of L-NAME (30 mg/kg IP) on SBP is compared in apoE(-/-) and controls, with (C57R, gray bars; apoE R, hatched bars) or without (C57, solid bars; apoE, open bars; n=6 in each group) rosuvastatin treatment. Hypertensive effect of L-NAME is selectively lost in apoE-/- and restored to control levels after 2 weeks of treatment with rosuvastatin. P<0.05 vs baseline in *C57, $C57 R, and #apoE R. B, Representative power spectra of SBP variability before and after L-NAME administration in a C57Bl/6 mouse. Note selective increase in SBP variability in VLF band after L-NAME (bold tracing). C, Absolute change in VLF energy band of SBP variability induced by L-NAME administration in apoE-/- and control mice before and after 2 weeks of treatment by rosuvastatin (same labels as in A; n=6 in each group). *P<0.05 vs C57Bl/6, C57 R, and apoE R.

Again, rosuvastatin (which had no effect in control mice) increased the absolute SBP change (Figure 4A) and SBP variability response (Figure 4C, hatched bar) to NOS inhibition in apoE^-/- mice (Figure 4, A and C, hatched bars).

ApoE^-/- Mice Have Increased Cardiac and Aortic Caveolin-1 Abundance That Correlates With SBP Variability
In apoE^-/- mice, the impaired sensitivity to NOS inhibition suggested alterations in NOS abundance, activity, or both. We quantified the expression of eNOS protein and of one key eNOS allosteric inhibitor, caveolin-1, in whole extracts of cardiac and aortic tissues from all groups of animals. ApoE^-/- mice had levels of immunoblotted eNOS similar to those in control animals. Rosuvastatin had no effect on eNOS abundance in either group of mice (not shown). As shown in Figure 5, caveolin-1 levels were increased by 2-fold in cardiac and aortic extracts of apoE^-/- mice (Figure 5, A and B). Rosuvastatin had no effect on caveolin-1 levels in C57Bl/6 mice but reduced caveolin-1 abundance to control levels in heart and aorta of apoE^-/- mice (Figure 5, A and B, hatched bars).

View larger version (17K): [in this window] [in a new window]   Figure 5. Effect of rosuvastatin on caveolin-1 expression in cardiac and aortic tissue of apoE-/- compared with control mice. Densitometric analysis of immunoblotted signals for caveolin-1 protein normalized to those of hsp 90 on same gels. Data are expressed as percent of normalized levels of caveolin-1 in cardiac (A) and aortic (B) tissues of C57Bl/6 mice. Labels as in Figure 2. Caveolin-1 levels were higher in cardiac and aortic extracts from apoE-/- mice. Rosuvastatin had no significant effect on caveolin-1 levels in control mice but reduced its abundance back to control levels in both tissues of apoE-/- mice. *P<0.05 vs C57Bl/6; #P<0.05 vs apoE-/- without rosuvastatin treatment.

Of note, parallel measurements of plasma lipid levels in the same animals revealed that plasma LDL cholesterol concentration remained elevated in rosuvastatin-treated apoE^-/- mice (386±101 versus 557±47 mg/dL; P=NS), as expected from previous experiments with rosuvastatin in this mouse strain.

Because caveolin-1 is a main regulator of eNOS activity in conduit arteries such as the aorta, we examined the correlation between aortic caveolin-1 levels and SBP variability in the VLF band, reflective of the NO buffering effect on BP (see Figure 4), across all groups of animals. A strong positive correlation (y=5.25x+47.5, r²=0.80) was observed between these 2 measures, as illustrated in Figure 6.

View larger version (13K): [in this window] [in a new window]   Figure 6. Relationship between aortic caveolin-1 expression and BP variability. Mean aortic caveolin-1 protein levels (expressed as fold increase over levels in control mice) were plotted against mean SBP variability in VLF band from 4 groups of mice (n=4 to 8 in all 4 groups). There was a strong correlation (y=5.25x+47.51, R2=0.78) between aortic caveolin-1 expression and VLF energy band of SBPV. C57Bl/6 (), apoE-/- (), C57Bl/6 plus rosuvastatin (), and apoE-/- plus rosuvastatin ().

	Discussion

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Abolition of circadian cycles of BP and HR in hypertensive animals,¹⁷ such as apoE^-/- mice in the present study (Table and Figure 1), have been generally associated with dysfunctions of the parasympathetic and/or sympathetic components of the arterial baroreflex.¹⁸ Using spectral analysis of BP and HR variability, several groups have identified the influence of neurohumoral or autonomic input on specific frequency bands of the variability spectra. The bandwidth characteristic of each component varies among animal species and was recently determined in mice.^10,14 We independently validated the influence of the parasympathetic component and of the NO pathway on our spectra using acute pharmacological inhibition with atropine and an NOS inhibitor, respectively. In control mice, we found that HR variability in the HF band was abrogated by atropine (Figure 3B), confirming its dependence on a functional parasympathetic system. In apoE^-/- mice, we then observed a basal (ie, without atropine) reduction of HR variability in this HF band (Figure 2C), suggesting a defective parasympathetic drive to the heart. In support of this interpretation, atropine had no further effect on HR variance in apoE^-/- mice (Figure 3C). Similar attenuated responses to atropine challenge have been observed in obese hypertensive dogs¹⁷ that exhibit altered resting and reflex parasympathetic control of HR.

HR and BP variabilities in the VLF band reflect the mixed influence of neurohumoral mechanisms. In addition, SBP variability in the VLF band also integrates the short-term buffering effect of NO.⁹ Accordingly, in our control mice, NOS inhibition increased SBP and its variability in the VLF band (Figure 4, A and B). A similar higher BP variability in the VLF band is distinctively observed in mice genetically deficient in eNOS.⁹ In apoE^-/- mice, SBP variability was markedly increased in the VLF band (Figure 2A), suggesting a defective NO control mechanism. Again, the effect of NOS inhibition on SBP (Figure 4A) and SBP variability in the VLF band (Figure 4C) was significantly attenuated in apoE^-/- mice, consistent with constitutive impairment of their NO buffering system. In addition, because endogenous NO has been implicated in the modulation of the parasympathetic input to the heart at the presynaptic¹⁹ and postsynaptic^20–22 levels, respectively, a defective cardiac NOS may also participate in the loss of HR variability in the HF band (as shown above) irrespective of the vasculature.

High LDL cholesterol can impair eNOS-dependent endothelial function (and subsequently increase SBP variability) in conduit arteries through a variety of mechanisms, some of which are specifically targeted by statin treatment.^23,24 Notably, some previous studies in apoE^-/- mice have found altered NO-dependent vasodilatation only at later stages of atherosclerosis development.^25,26 They did not examine intermediate time points closer to the 3 months used here. Yang et al,²⁶ for example, found increased BP and impaired cutaneous hyperemia to mustard oil application at 7.5 months but not 6 weeks of age. However, the neurogenic vasodilatation to mustard oil is less specific for endothelial eNOS function,²⁷ and the sensitivity of their BP recordings 24 hours after catheter implantation may have been hampered by residual effects of anesthesia/surgery, as previously demonstrated.²⁸ In addition to changes in eNOS expression, alterations in eNOS-dependent vasodilatation may involve posttranscriptional regulation of the activity of the enzyme through allosteric interactions with other proteins, such as the caveolar coat protein, caveolin-1, that represses eNOS activation.^13,29 The functional relevance of these protein-protein interactions in vivo is best illustrated by the phenotype of caveolin-1–deficient mice, which exhibit a vascular hyporesponsiveness to vasoconstrictor agonists because of de-repressed eNOS activity.^30,31 Conversely, eNOS activity is impaired on increased expression of caveolin-1 in endothelial cells, such as obtained on exposure to native LDL cholesterol.¹² In addition, oxidized LDL particles may also independently alter eNOS abundance³² or subcellular localization.³³ In our hands, the effect of native LDL on caveolin-1 was fully reversed on inhibition of cholesterol synthesis in endothelial cells with a statin.¹⁵ We therefore examined the possibility that hemodynamic alterations in dyslipidemic, apoE^-/- mice were associated with similar changes in caveolin-1 and/or eNOS abundance that would be sensitive to chronic treatment with rosuvastatin. We found that caveolin-1 content was increased in aortic and cardiac tissues of apoE^-/- mice (compared with C57Bl/6 controls; Figure 5), whereas eNOS abundance was unchanged. The abundance of aortic caveolin-1 also positively correlated with increased variability of SBP in the VLF band (Figure 6), suggesting the negative functional impact of caveolin-1 upregulation on the buffering capacity of eNOS on SBP. The notion that these expressional changes in aortic caveolin-1 may have an impact on NOS function in apoE^-/- mice in vivo is supported by the insensitivity of these animals to the NOS inhibitor (Figure 4, A and C). Under our treatment conditions, rosuvastatin did not alter eNOS expression but reduced caveolin-1 expression to control levels (Figure 5). The statin also restored the effect of NOS inhibition in the same animals, suggesting a restoration of NOS function even in the absence of changes in eNOS abundance.

Consistent with the previous identification of sterol regulatory elements in the caveolin-1 gene promoter³⁴ and our previous data in vitro,¹⁵ rosuvastatin may exert its effect through transcriptional regulation of caveolin-1 expression. This does not exclude potential additional effects of the drug to enhance NOS signaling in vivo or other effects of the statin on HR or BP variability independent of NOS regulation. From our analysis in whole-tissue extracts, caveolin-1 downregulation is presumed to be at the endothelial cell level but could be in smooth muscle or other cell type(s). Unlike our previous observations in cultured endothelial cells, statin treatment had no effect in the control (ie, low LDL cholesterol) condition. Whether this is because of specific biological parameters in vivo or simply the consequence of a lesser sensitivity to detect a decrease from whole-tissue extracts with a lower caveolin pool in normocholesterolemic animals remains undetermined.

Notably, the hemodynamic improvements with rosuvastatin were observed despite the persistence of high plasma LDL cholesterol. This is in keeping with the clinical beneficial effects observed with other statins regardless of cholesterol level,³⁵ which add to the growing body of evidence suggesting that statins confer a therapeutic benefit beyond lipid lowering.^36,37 The effect on BP demonstrated in our study would seem to be relevant to the cardiovascular benefit in patients, because statins can reduce BP in humans.^38,39 Restoration of vagal and NOS-mediated regulation with statins would be particularly important in high-risk (including hypercholesterolemic) patients, given the adverse prognostic impact of altered HR and BP variability.² Whether such benefit might be extended to patients experiencing HR and BP disorders from causes other than dyslipidemia (such as heart failure^40,41) will require further testing.

	Acknowledgments

 
This study was supported by funding from the Fond Special de la Recherche (Prix FSR) of the University of Louvain (Dr Pelat), an Action de Recherche Concertée (ARC-01/06-271) from the Communauté Française de Belgique (Drs Balligand and Feron), a Pole d’Attraction Interuniversitaire (PAI-P5/02) from the Belgian Federal Services for Scientific Affairs (Dr Balligand), and the Fonds National de la Recherche Scientifique (FNRS). Drs Feron and Dessy are Research Associates of the FNRS. We express special thanks to Delphine DeMulder for excellent technical assistance.

Received December 17, 2002; accepted February 3, 2003.

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