(Circulation. 2001;103:2598.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa (R.S., A.M.L.); the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, La (M.E.G., S.P.J., M.H., D.M.R., S.D.T., M.B.S., D.J.L.); and the Cardiovascular Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Mass (P.L.H.).
Correspondence to David J. Lefer, PhD, Department of Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail dlefer{at}lsuhsc.edu
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Abstract |
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Background—Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE–/–) mice fed a high-cholesterol diet.
Methods and Results—We studied leukocyte-endothelium interactions in apoE–/– mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE–/– mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE–/– mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE–/– mice (P<0.001 versus control diet) were significantly attenuated by simvastatin treatment (P<0.01 versus vehicle). Cholesterol-fed apoE–/– mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis (P<0.01 versus control diet), which was significantly attenuated by simvastatin (P<0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE–/– mice.
Conclusions—Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.
Key Words: endothelium • hypercholesterolemia • reperfusion • nitric oxide
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Introduction |
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The major action of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (simvastatin, pravastatin, etc), which are collectively known as "statins," is the inhibition of cholesterol synthesis in the liver.1 Recently, Vaughan et al2 suggested that several statins may exert effects that are distinct from their cholesterol-lowering actions. In this regard, it has been shown that simvastatin can extend the half-life of nitric oxide synthase (NOS) mRNA in endothelial cells in vitro under cholesterol-clamped conditions.3 Other investigators have shown that by increasing the bioavailability of NO in the vascular endothelium of normocholesterolemic animals, statins inhibit leukocyte-endothelium interactions in the microcirculation.4 As a result of these endothelial-preserving effects, statins can ameliorate neural injury during cerebral ischemia5 and protect the ischemic-reperfused myocardium from polymorphonuclear neutrophil (PMN)-mediated injury.6 These findings provide convincing evidence that statins can improve endothelial function and protect the cardiovascular system in normocholesterolemic subjects, independent of their cholesterol-lowering effects.
However, the highest incidence of coronary artery disease is observed in humans who have a long-standing history of hypercholesterolemia, including those who are affected by severe forms of familial hypercholesterolemia.7 8 To our knowledge, no data are available demonstrating that short-term statin therapy can exert anti-inflammatory effects or protect tissue in the setting of severe hypercholesterolemia.
Therefore, we tested the hypothesis that a widely used HMG-CoA reductase inhibitor, simvastatin, can inhibit leukocyte-endothelium interactions in the microcirculation of a genetic mouse model of hypercholesterolemia and can protect the myocardium of hypercholesterolemic mice against ischemia-reperfusion injury. In the present study, we used the apoE–/– mouse, a well-established genetic mouse model of atherogenic hypercholesterolemia, which is similar to hyperlipoproteinemia type III in humans.9 The study was designed so that blood cholesterol levels were not affected by statin treatment. We also used NOS gene-targeted mice to help determine the mechanism of action of short-term simvastatin therapy.
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Methods |
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This study was performed in accordance with the National Institutes of Health guidelines for the use of experimental animals. All animal protocols were approved by the Institutional Animal Care and Use Committee of Thomas Jefferson University and the Animal Care and Use Committee of Louisiana State University Health Sciences Center.
Animal Protocols and Preparation of
Simvastatin
ApoE–/– mice, 4 to 6
months of age (Jackson Laboratory, Bar Harbor, Maine), either were fed
a high-cholesterol diet for 2 consecutive weeks (15.8% fat
and 1.25% cholesterol; from Harlan Teklad) or were
maintained on noncholesterol-fortified chow for an equal
duration of time. Mice were then randomly divided into 1 of the
following 3 groups: (1) apoE–/– mice fed a
normal diet and given vehicle, (2) apoE–/–
mice fed a high-cholesterol diet and given vehicle, and (3)
apoE–/– mice fed a
high-cholesterol diet and given simvastatin.
Simvastatin was obtained from Merck Inc and was chemically
activated by alkaline treatment before use, as previously
described.10
Simvastatin (1 mg/kg SC) was administered to the
apoE–/– mice 18 hours before study. At the
end of the 2-week high-cholesterol feeding, mice were
either used for intravital microscopy studies or subjected to in vivo
myocardial ischemia and reperfusion.
In additional studies, wild-type mice (C57BL/6, Jackson Labs), endothelial NOS (eNOS)-deficient mice (Paul Huang, Harvard University, Boston, Mass), and inducible NOS (iNOS)-deficient mice (Jackson Labs) were treated with simvastatin (1 mg/kg) or an equal volume of vehicle 18 hours before myocardial ischemia.
Intravital Microscopy
Intravital microscopy of mouse peri-intestinal
venules was performed according to previously described
methods11 in
pentobarbital-anesthetized mice. The ileum and mesentery of
anesthetized animals were placed in a temperature-controlled
Plexiglas chamber, and a modified
Krebs-Henseleit solution was used to superfuse the mouse intestine. Red
blood cell velocity was determined online using an optical Doppler
velocimeter.12
Myocardial Ischemia-Reperfusion
Surgical Procedures
The surgical protocol and infarct size determination
were performed according to methods described
previously.13 The mice were
anesthetized with sodium pentobarbital (50 mg/kg IP) and
ketamine (50 mg/kg IP). After the surgical procedure, mice were
given butorphanol tartrate (
0.08 mg/kg SC) for analgesia. The
animals were given supplemental oxygen (100%) via a nasal cone, and
they were allowed to recover in a temperature-controlled
area.
Determination of Area at Risk and Infarct
Size
After 24 hours of reperfusion, the mice were
connected to a ventilator, the left anterior descending
coronary artery was re-ligated, and Evans blue (1.2 mL of 1.0%
solution) was retrogradely infused into the carotid artery catheter to
delineate the ischemic zone from the nonischemic zone.
The heart was serially sectioned along its long axis and incubated in
1.0% of 2,3,5-triphenyltetrazolium
chloride for 5 minutes at 37°C to allow differentiation between the
viable and necrotic areas of the myocardium previously
rendered ischemic. Each of the five 1-mm-thick slices was
weighed, and the areas of infarction, risk, and nonischemic
left ventricle were assessed by a blinded observer using
computer-assisted planimetry (NIH Image
1.57).
Assessment of Myocardial Neutrophil
Infiltration
Routine histological staining was
performed on multiple sections of midventricular cardiac
sections to determine the extent of PMN infiltration. For each heart,
the number of PMNs was counted in 12 fields of 3 independent tissue
sections by a blinded observer.
Quantification of NO Released From Isolated
Aortic Tissue
Freshly isolated thoracic aortas were isolated from
wild-type and apoE–/– mice. Freshly
dissected aortic rings measuring 5 to 6 mm in length were cut,
opened from random segments of the aorta, and fixed by small pins with
the endothelial surface up in 24-well culture dishes
filled with 1 mL of Krebs-Henseleit solution. After equilibration at
37°C, NO released into the Krebs-Henseleit solution was measured by
means of a shielded polarographic NO electrode connected to a NO meter
(Iso-NO Mark II, World Precision Instruments), according to a
previously described
method.14
Statistical Analysis
All data are presented as mean±SEM. Data on
mean arterial blood pressure, venular shear rates,
leukocyte rolling, and adherence were compared by ANOVA using Fisher’s
post hoc analysis. Myocardial necrosis and PMN counts (between
groups) were analyzed with a 2-tailed unpaired
t test. All statistics were
calculated with StatView 4.5 (Abacus Concepts). Probabilities of 0.05
or less were considered
significant.
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Results |
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Effect of Simvastatin on Blood Cholesterol Levels
Wild-type mice exhibited total cholesterol levels <100 mg/dL and were unaffected by 18 hours of simvastatin treatment (Figure 1
). ApoE–/– mice that
were maintained on a high-cholesterol diet exhibited
elevated total blood cholesterol levels (2769±210 mg/dL)
compared with apoE–/– mice fed normal chow
(343±21 mg/dL; P<0.001).
Administration of a single dose of simvastatin to
cholesterol-fed apoE–/– mice
did not significantly lower their elevated blood
cholesterol levels.
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Leukocyte-Endothelium
Interaction in the Microcirculation
We examined mouse peri-intestinal venules ranging from
33 to 39 µm in diameter; there was no significant difference in
venular diameter among any of the groups studied. The mean venular
shear rates were also similar in all groups, ranging from 685±81 to
710±64 s–1. Mean arterial
blood pressures ranged between 99±16 and 105±10 mm Hg
over the 60-minute observation period, and they did not differ
significantly among groups. Thus, the adhesive interactions observed
between circulating leukocytes and the microvascular
endothelium were not due to changes in
hemodynamics brought about by high
cholesterol feeding or by the subcutaneous administration
of simvastatin 18 hours earlier.
Wild-type mice, whether given simvastatin or
not, exhibited low levels of leukocyte rolling
(Figure 2) and a low number of adherent leukocytes
(Figure 3). Investigation of peri-intestinal venules in
apoE–/– mice revealed that leukocyte
rolling doubled and adherence increased nearly 4-fold in
apoE–/– mice
(Figure 3) compared with wild-type controls. Moreover, at the
end of the 2 weeks of high cholesterol feeding, both
leukocyte rolling and firm adhesion increased nearly 2-fold compared
with apoE–/– mice fed a control diet.
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In contrast, simvastatin markedly attenuated
both leukocyte rolling
(Figure 2
) and adherence
(Figure 3) in cholesterol-fed
apoE–/– mice
(P<0.05 versus
cholesterol-fed apoE–/– mice
given vehicle). Therefore, systemic administration of
simvastatin to apoE–/– mice
exposed to a high-cholesterol diet for 2 weeks inhibited
leukocyte-endothelium interaction, even in the absence
of significant cholesterol lowering.
Effect of Simvastatin on Myocardial
Ischemia-Reperfusion
Myocardial Area at Risk and Necrosis
Experiments in which wild-type controls were treated
with simvastatin and then subjected to the myocardial
ischemia-reperfusion protocol are shown in
Figure 4A. The areas of left ventricle placed at risk for
infarction by coronary artery occlusion were similar in both
groups of wild-type controls. Pretreatment with simvastatin
significantly (P<0.01) reduced
the extent of myocardial necrosis in wild-type mice.
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Despite similar areas at risk, hearts from
cholesterol-fed apoE–/– mice
given vehicle suffered a significantly larger area of infarction after
myocardial ischemia-reperfusion compared with both control
diet–fed apoE–/– mice and
cholesterol-fed apoE–/– mice
given simvastatin. Summary data for areas at risk and
amount of myocardial necrosis in apoE–/–
mice are shown in
Figure 4B. All groups of animals experienced similar-sized
areas at risk per left ventricular area. The areas at risk
were 54% to 57% of the left ventricle for all groups of mice
subjected to myocardial ischemia/reperfusion. Thus, the
exposure of apoE–/– mice to high
cholesterol feeding for 2 weeks resulted in increased
myocardial injury after ischemia and reperfusion, and this was
attenuated by a noncholesterol-lowering treatment with
simvastatin.
The cardioprotection provided by simvastatin was
influenced by the bioavailability of different isoforms of NOS, as
depicted in the
Table.
Thus, mice deficient in eNOS (eNOS–/–
mice) exhibited markedly exacerbated myocardial necrosis
(P<0.05 versus wild-type
controls). Moreover, this cardiac reperfusion injury was unaffected by
simvastatin treatment
(Table).
In iNOS–/– mice, the degree of cardiac
necrosis was comparable to that in the wild-type mice, but
simvastatin did not influence this degree of injury
(Table).
Thus, NO seems to play a key role in the cardioprotective effects of
simvastatin. Both eNOS and iNOS seem to contribute to the
enhanced NO released by simvastatin, although the
contribution by eNOS seems to be somewhat
greater.
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Myocardial PMN Accumulation
The degree of infiltrated PMNs into the
ischemic-reperfused myocardium after 30 minutes of
myocardial ischemia and 24 hours of reperfusion is
presented in
Figure 5. Twenty-four hours after reperfusion, PMN
accumulation in ischemic-reperfused myocardium was
52±2 PMNs/field in wild-type mice
(Figure 5A). Accumulation was only 21±1
PMNs/mm2 in hearts taken from wild-type mice
given simvastatin
(P<0.01). The number of
PMNs/mm2 in hearts from
apoE–/– mice fed the control diet was
54±3 PMNs/mm2. This value increased by 40%
in apoE–/– mice fed a
high-cholesterol diet
(Figure 5B; P<0.01).
In contrast, systemic administration of simvastatin to
cholesterol-fed apoE–/– mice
attenuated the number of neutrophils infiltrating into the
ischemic/reperfused myocardium by 45%
(P<0.01 versus
cholesterol-fed apoE–/– mice
given vehicle). These data closely correlate with data on leukocyte
adherence obtained by intravital microscopy, and they also demonstrate
a marked antiadhesive effect of simvastatin in the
microcirculation of cholesterol-fed
apoE–/–
mice.
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Effect of Simvastatin on
Endothelial NO Release
We also measured NO release from aortic segments
isolated from vehicle- and simvastatin-treated
apoE–/– mice fed either a control or a
high-cholesterol diet. Wild-type mice exhibited a NO
release of 22±4 nmol/g tissue, and this increased by 53% after
simvastatin treatment
(Figure 6). We detected a slightly reduced basal level of NO
release in aortic rings isolated from
apoE–/– mice fed a control diet
(Figure 6). However, exposure of
apoE–/– mice to
high-cholesterol diet for 2 weeks significantly reduced the
basal release of NO to half of control values
(P<0.02 versus control diet
mice). However, 18 hours after the injection of 1 mg/kg
simvastatin into cholesterol-fed
apoE–/– mice, the basal release of NO
measured in aortic rings increased to double the values observed in
apoE–/– mice fed a normal diet
(Figure 6). Although not shown in
Figure 6, the addition of 100 µmol/L of
N-nitro-L-arginine methyl
ester, a NOS inhibitor, reduced NO values in all groups to
approximately zero. Therefore, systemic administration of a single dose
of simvastatin to either wild-type or
apoE–/– mice significantly increased
endothelium-derived NO over a period of 18
hours.
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Discussion |
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Endothelial cell dysfunction is one of the earliest events occurring during hypercholesterolemia,15 16 and it ultimately contributes to the development of overt atherosclerosis.17 18 This endothelial dysfunction is characterized by a marked reduction in biologically active NO released from the vascular endothelium, which can predispose the circulation to coronary artery disease. Increased hypercholesterolemia in rabbits in the absence of atherosclerotic plaque formation has been shown to exacerbate reperfusion injury after myocardial ischemia and reperfusion.19 20 Moreover, several animal and human studies17 21 indicate an improvement in endothelial function associated with the lowering of serum cholesterol.
One widely used means of controlling hypercholesterolemia is HMG-CoA reductase inhibitors (statins). Statins lower blood cholesterol levels by inhibiting the hepatic biosynthesis of cholesterol at the mevalonate step.1 This reduced cholesterol synthesis normalizes endothelial function in animals17 and humans22 23 and results in reduced coronary artery disease21 23 and stroke.24 These effects are apparently due to reduced cholesterol accumulation in endothelial cells and, consequently, to preservation of endothelial function, including maintenance of NO release.
More recently, statins reportedly directly increased NOS activity in cultured endothelial cells under cholesterol-clamped conditions.3 In normocholesterolemic animals, this action of statins is associated with the inhibition of leukocyte-endothelium interaction in the microcirculation,4 attenuation of myocardial ischemia-reperfusion injury,6 and stroke protection.5
These findings clearly point toward an action other than cholesterol lowering by statins. However, it is unknown whether the noncholesterol-lowering effects of statins have therapeutic significance in chronic hypercholesterolemic conditions. In this study, simvastatin administered to cholesterol-fed apoE–/– mice exerted a marked cardioprotective effect without lowering blood cholesterol levels. Our data also show that short-term treatment with statins exerts a distinct anti-inflammatory effect within the cardiovascular system, as demonstrated by attenuated neutrophil-endothelium interactions in the microvasculature and the reduced infiltration of neutrophils into the ischemic-reperfused myocardium of cholesterol-fed apoE–/– mice. This early anti-inflammatory effect of simvastatin was associated with enhanced NO release from the vasculature of cholesterol-fed apoE–/– mice. These findings are consistent with previous observations showing that simvastatin upregulates eNOS activity in endothelial cells by inhibiting the degradation of eNOS mRNA.3
In the present study, we extended our knowledge of the source of enhanced NO production by simvastatin. We presented data in this study showing that simvastatin-stimulated NO production occurs, to a large extent, from eNOS, but iNOS can also contribute to this process. Because iNOS is present in vascular smooth muscle cells, this may represent an augmentation of NO production by vascular components other than endothelium.
Several possibilities may explain the cardiovascular protective effects of statins, even in the absence of reduced blood cholesterol levels. These mechanisms all relate to the preservation of endothelial function, the inhibition of neutrophil-mediated tissue injury, or a combination of these 2 effects. Statins have been shown to stabilize eNOS mRNA, thus increasing the bioavailability of NO in cultured endothelial cells3 and in normocholesterolemic animals.4 6 In the present study, we showed for the first time that simvastatin significantly and acutely increases basal NO release from the vascular endothelium of genetically hypercholesterolemic animals by a specific mechanism involving NOS. NO has been shown to act as a physiological immunomodulator that can inhibit leukocyte-endothelium interaction25 by suppressing the upregulation of several endothelial cell adhesion molecules.26 27 Therefore, the maintenance of endothelium-derived NO may be a very important aspect of the cardioprotective effects of simvastatin. Although one cannot directly visualize the coronary microcirculation in vivo, all indications are that comparable events occur in the more readily visualized splanchnic microcirculation.
Salutary effects have been observed with simvastatin and lovastatin in mice subjected to cerebral ischemia-reperfusion.5 These effects were specifically dependent on enhanced NO formation because they did not occur in eNOS–/– mice28 and they were unrelated to the inhibitory effect of simvastatin on cholesterol biosynthesis. This endothelial preservation, with its subsequent attenuation of neutrophil activation, effectively prevents neutrophil-induced cardiac dysfunction.6 In previous work, we provided evidence that simvastatin significantly increases basal NO release from the normocholesterolemic vascular endothelium by a specific mechanism involving NOS.6 This increased bioavailability of NO induced by statins attenuates the upregulation of cell adhesion molecules both in the coronary microvascular endothelium6 and in the mesenteric microvasculature,4 thus limiting neutrophil adherence to the endothelium during inflammatory conditions.
In conclusion, therapeutic administration of statins during severe hypercholesterolemia may promote endothelial preservation and normalize vascular homeostasis before lowering cholesterol. These salutary effects were obtained with clinically used doses (ie, equivalent to 75 mg, single dose in a human subject), and these effects might represent a new strategy for the primary prevention of short and long-term inflammatory states in coronary artery disease, as was previously suggested in a large multicenter clinical study.29
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Acknowledgments |
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Supported by research grants from Merck to A.M.L. and D.J.L., research grant #1-2000-68 from the Juvenile Diabetic Foundation to R.S., and research grants #RO1-HL-60849 and P01-DK-43785 from the National Institutes of Health to D.J.L..
Received October 23, 2000; revision received January 12, 2001; accepted January 23, 2001.
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A. Tailor, D. J. Lefer, and D. N. Granger HMG-CoA reductase inhibitor attenuates platelet adhesion in intestinal venules of hypercholesterolemic mice Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1402 - H1407. [Abstract] [Full Text] [PDF]
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M. A. Hernandez-Presa, M. Ortego, J. Tunon, J. L. Martin-Ventura, S. Mas, L. M. Blanco-Colio, C. Aparicio, L. Ortega, J. Gomez-Gerique, F. Vivanco, et al. Simvastatin reduces NF-{kappa}B activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet Cardiovasc Res, January 1, 2003; 57(1): 168 - 177. [Abstract] [Full Text] [PDF]
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M. Takemoto and J. K. Liao Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1712 - 1719. [Abstract] [Full Text] [PDF]
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