© 1999 American Heart Association, Inc.
Vascular Biology |
Simvastatin Inhibits Leukocyte–Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Dr Allan M. Lefer, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799. E-mail Allan.M.Lefer{at}mail.tju.edu
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Abstract |
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Abstract—Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte–endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 µg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 50 µmol/L) significantly increased leukocyte rolling from 12±2 to 60±8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8±0.5 to 17±1.2 leukocytes per 100 µm of venular length, and raised leukocyte transmigration from 2.5±1.0 to 10±2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 µg per rat IP) significantly attenuated L-NAME–stimulated leukocyte rolling, to 12±2 (P<0.01); adherence, to 5±0.5 leukocytes per 100 µm (P<0.01); and leukocyte transmigration, to 3.5±1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte–endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.
Key Words: HMG-CoA reductase inhibitors • P-selectin • leukocyte rolling • leukocyte transmigration • nitric oxide
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Introduction |
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The discovery of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the 1980s and their clinical use as therapeutic agents1 have resulted in widespread treatment of hyperlipidemia and coronary artery disease. The major mechanism of the HMG-CoA reductase inhibitors (ie, simvastatin, lovastatin, pravastatin, etc), commonly referred to simply as the "statins," is the inhibition of cholesterol synthesis in the liver by blocking the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis.2 Clinical trials have shown that HMG-CoA reductase inhibitors reduce cholesterol levels, which can be correlated with improved survival rates in patients with coronary artery disease.3 4 5 6 Lowering cholesterol levels in patients with high cholesterol levels reduces their risk of coronary and cerebrovascular events.6 7 However, treatment with HMG-CoA reductase inhibitors of coronary artery disease patients who have average cholesterol levels has also demonstrated a significant benefit in terms of cardiovascular and cerebrovascular events.7 Moreover, Kimura et al8 demonstrated that the HMG-CoA reductase inhibitor fluvastatin significantly reduced platelet-activating factor– and leukotriene B4–induced inflammatory responses without altering serum cholesterol levels in hypercholesterolemic rats. Nevertheless, it is not entirely clear whether coronary and cerebrovascular events can be prevented by statins owing to their cholesterol-lowering effects or by some other actions. In this connection, HMG-CoA reductase inhibitors were recently shown to exert effects unrelated to their well-known cholesterol-lowering actions.9 10 One potentially important non–cholesterol-lowering effect of the statins appears to be upregulation of endothelial nitric oxide (NO) synthase.9
In a variety of cardiovascular disorders such as ischemia-reperfusion,11 circulatory shock,12 and atherogenesis,13 endothelial function is markedly impaired.14 This endothelial dysfunction is characterized by a loss in the ability of the endothelium to synthesize and release NO. This inability to produce NO is critical in the development and progression of tissue injury, since NO has been shown to modulate vascular tone,15 inhibit platelet activation,16 and attenuate neutrophil adherence.17 Decreased release of basal NO leads to a cascade of pathophysiological events resulting in neutrophil infiltration into inflamed tissues. It is known that this process is regulated by a complex interplay among adhesion molecules (ie, selectins, integrins, and immunoglobulin superfamily members). P-selectin, a key member of the selectin family of adhesion glycoproteins, is rapidly translocated from Weibel-Palade bodies to the endothelial cell surface when these cells are activated due to hypoxia-reoxygenation, increased oxygen-derived free radicals, histamine, or thrombin.18 19 P-selectin is involved in the early stages of the leukocyte-endothelium adhesion cascade and promotes leukocyte rolling, which enables adherence to the endothelium, subsequent transendothelial migration,20 and recruitment of leukocytes into injured tissue,21 22 the end result of which contributes to further tissue injury in inflammatory states.23
Therefore, we have examined the effects of a widely used statin (ie, simvastatin) at doses equivalent to those used orally in humans on leukocyte-endothelium interactions in vivo under normocholesterolemic conditions. We assessed the effects of this statin on leukocyte rolling, leukocyte adherence to the endothelium, and leukocyte transmigration across the endothelium by the use of intravital microscopy. We also related these effects of simvastatin to P-selectin expression in postcapillary venules under local inflammatory states.
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Methods |
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Intravital Microscopy
Male Sprague-Dawley (ACE, Boyertown, PA) rats weighing 250 to 275 g were anesthetized with sodium pentobarbital (60 mg/kg IP). A tracheotomy was performed to maintain a patent airway throughout the experiment. A polyethylene catheter was inserted into the left carotid artery. Mean arterial blood pressure was continuously recorded on a Grass model 7 oscillographic recorder and a Statham P23AC pressure transducer (Gould). The left jugular vein was cannulated for supplementary administration of sodium pentobarbital to maintain a surgical plane of anesthesia throughout the experiment. All experiments were approved by the Thomas Jefferson University Animal Care Committee.
A loop of ileal mesentery was exteriorized through a midline incision and placed in a temperature-controlled, fluid-filled Plexiglas chamber for observation of the mesenteric microcirculation by intravital microscopy.24 The ileum and mesentery were superfused throughout the experiment with a modified Krebs-Henseleit solution of the following composition (in mmol/L): 118 NaCl, 4.74 KCl, 2.45 CaCl2, 1.19 KH2PO4, 1.19 MgSO4, and 12.5 NaHCO3 warmed to 37°C and bubbled with 95% N2 and 5% CO2. Red blood cell velocity was determined online by using an optical Doppler velocimeter23 obtained from the Microcirculation Research Institute, College Station, Tex. This method gives an average red blood cell velocity that can be digitally displayed on a meter and allows for the calculation of shear rates. Red blood cell velocity (V) and venular diameter (D) were used to calculate venular shear rate (g) with the formula g=8(Vmean/D), where Vmean=V/1.6.25
The rats were allowed to stabilize for 20 to 30 minutes after surgery. After stabilization, a 30- to 50-µm-diameter postcapillary venule was chosen for observation. A baseline recording was made to establish basal values for leukocyte rolling, adherence, and the number of transmigrating leukocytes. Video recordings were made at 30, 60, 90, and 120 minutes after initiation of the mesentery superfusion for quantification of leukocyte rolling, adherence, and transmigration. The number of rolling and adherent leukocytes was determined offline by playback analysis of videotape taken from a video camera and videocassette recorder. Leukocytes were considered to be rolling if they were moving at a velocity significantly slower than the red blood cells. Leukocyte rolling is expressed as the number of cells moving past a designated point per minute (ie, leukocyte flux). A leukocyte was judged to be adherent if it remained stationary for >30 seconds.26 Adherence is expressed as the number of leukocytes adhering to the endothelium per 100 µm of vessel length. To quantify the number of transmigrated leukocytes, the tissue area adjacent to the 100-µm length of postcapillary venule over a distance of 20 µm from the vessel wall was used. The number of extravasated leukocytes was counted and normalized with respect to this area.
Immunohistochemistry
After completion of the intravital microscopy, the superior
mesenteric artery and vein were cannulated for perfusion of the small
bowel. The ileum was first washed free of blood by perfusion with
Krebs-Henseleit buffer warmed to 37°C and bubbled with 95%
O2 and 5% CO2. Once the
venous perfusate was free of red blood cells, perfusion was
initiated with iced 4% paraformaldehyde mixed in
phosphate-buffered 0.9% NaCl for 5 minutes. Rats were then euthanized
by intravenous injection of 90 mg/kg sodium pentobarbital. A 3- to 4-cm
segment of ileum was isolated from the perfused intestine and fixed in
4% paraformaldehyde for 90 minutes at 4°C.
Tissue sections were embedded in plastic (Immunobed,
Polysciences Inc), and 4-µm-thick sections were cut and transferred
to Vectabond-coated slides (Vector Laboratories). Immunohistochemical
localization of P-selectin was accomplished by using the avidin/biotin
immunoperoxidase technique (Vectastain ABC reagent, Vector
Laboratories) and monoclonal antibody PB1.3 against P-selectin exposed
on the endothelial cell surface, as previously
described.27 This monoclonal antibody stains
surface-expressed P-selectin only.27 Four rats were
studied in each group, and 50 venules were analyzed per tissue
section, with 10 sections examined per rat. The percentage of
P-selectin–positive staining was thus determined on 500 venules
per rat.
Experimental Protocols
Simvastatin is an inactive prodrug and therefore was
activated by alkaline hydrolysis as previously
described.9 Rats were randomly divided into 1 of several
groups: (1) Krebs-Henseleit–superfused mesenteries, (2) mesenteries
superfused with 50 µmol/L
NG-nitro-L-arginine
methyl ester (L-NAME), (3) mesenteries superfused with 0.5 U/mL
thrombin, (4) rats injected with 12.5 µg of simvastatin
in 1.0 mL 0.9% NaCl intraperitoneally 18 hours
before intravital microscopy, (5) rats injected with 25 µg of
simvastatin as above, and (6) rats injected with 1.0 mL of
0.9% NaCl as above. In groups 4 through 6, the rats were subjected to
superfusion of the mesentery with either Krebs-Henseleit solution
alone, 50 µmol/L L-NAME, or 0.5 U/mL thrombin. The concentration
of L-NAME used only partially inhibited the synthesis of NO.
Data Analysis
All data are presented as mean±SEM. Data were compared
by ANOVA with post hoc analysis with Fisher’s corrected
t test. All data on leukocyte rolling, adherence, and
transmigration, as well as on arterial blood pressure and
shear rates, were analyzed by ANOVA for repeated measurements.
Probabilities of 0.05 or less were considered statistically
significant.
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Results |
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Intravital Microscopy
Superfusion of the rat mesenteries with Krebs-Henseleit buffer or with either of the 2 different stimuli tested (ie, L-NAME and thrombin) did not cause any significant systemic or local vascular effect. Mean arterial blood pressure ranged from 132±10 to 148±8 mm Hg in all experimental groups of rats and did not change significantly over the 2-hour observation period. Similarly, shear rates ranged from 515±21 to 483±30 s-1 in all experimental groups of rats and did not change significantly over the 2-hour observation period. This result clearly indicated that neither 50 µmol/L L-NAME nor 0.5 U/mL thrombin, locally applied to the rat mesentery, exerted any nonspecific effects in physical hydrodynamic forces and that the adhesive interactions observed between leukocytes and endothelial cells were not due to rheological factors.
Superfusion of the rat mesentery with either 50 µmol/L L-NAME or
0.5 U/mL thrombin resulted in a time-dependent increase in leukocyte
rolling and adherence in postcapillary venules of the mesenteric
vasculature. In contrast, pretreatment with simvastatin (25
µg IP, 18 hours before the study) significantly inhibited leukocyte
rolling and adherence in both L-NAME– and thrombin-stimulated groups.
The effects of simvastatin on the time course of
L-NAME–induced leukocyte rolling and adherence are shown in Figures 1
and 2.
The increase in leukocyte rolling and adherence was statisti-cally
significant as early as 30 minutes after the onset of superfusion with
50 µmol/L L-NAME (P<0.05 versus control rats) and
reached a value 5- to 6-fold above initial values at 120 minutes
(P<0.01). In contrast, administration of 25 µg of
simvastatin significantly inhibited the number of rolling
and adherent leukocytes along the venular endothelium
beginning 30 minutes after the onset of L-NAME superfusion.
Pretreatment with 12.5 µg of simvastatin only slightly
diminished the numbers of rolling and adherent leukocytes after L-NAME
superfusion, and this effect was not statistically significant.
Similarly, superfusion of the rat mesentery with 0.5 U/mL thrombin also
demonstrated a significant progressive increase in leukocyte rolling
(Figure 3) and adherence(Figure 4) 30 to 120 minutes after the onset of
thrombin superfusion. Simvastatin (25 µg) significantly
attenuated both leukocyte rolling and adherence in response to thrombin
stimulation.
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In rats superfused with Krebs-Henseleit solution, a small number of
transmigrated leukocytes was observed at 120 minutes in the mesenteric
extravascular space (within 20 µm of the postcapillary wall;
Figures 5A and 5B). However, in
vehicle-treated rats superfused with either 50 µmol/L L-NAME or
0.5 U/mL thrombin, the number of migrated leukocytes in the surrounding
tissue was significantly increased by 6-fold (P<0.01).
Pretreatment with 25 µg of simvastatin 18 hours before
the study significantly attenuated the number of extravasated
leukocytes after superfusion with either L-NAME (50 µmol/L) or
thrombin (0.5 U/mL). In contrast, a lower dose of
simvastatin (12.5 µg per rat) given 18 hours before
superfusion did not significantly retard the number of L-NAME– or
thrombin-stimulated rolling (Figures 1
and 3), adherent
(Figures 2 and 4), and transmigrated (Figures 5A and 5B) leukocytes along the postcapillary venules.
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Immunohistochemical Localization of P-Selectin
Immunostaining was used to investigate the extent
of surface expression of P-selectin in rat intestinal venules after
stimulation with either L-NAME (50 µmol/L) or thrombin (0.5
U/mL). Figure 6 summarizes the
immunohistochemical data for P-selectin expression as a percentage of
positive-staining venules. P-selectin positivity was studied on the
venular endothelium of the rat ileum in close proximity
to the mesentery. No adherent platelets were observed on the
intestinal microvascular endothelium. The percentage of
venules staining positively for P-selectin in control rats superfused
with Krebs-Henseleit buffer only was consistently low (<20%).
In contrast, P-selectin expression on the venular
endothelium was increased >4-fold, to 80% in L-NAME–
(Figure 6A) and thrombin- (Figure 6B) stimulated
mesenteries (P<0.01). Pretreatment with
simvastatin significantly attenuated P-selectin surface
expression as determined after stimulation with either L-NAME
(P<0.02) or thrombin (P<0.05). These data
clearly indicate that simvastatin significantly diminished
P-selectin expression in vivo on the venular
endothelial cell surface of the rat mesenteric
microvasculature and suggest a significant role for P-selectin in
leukocyte-endothelium interactions.
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Discussion |
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HMG-CoA reductase inhibitors (statins) are used clinically for lowering hypercholesterolemia because of their inhibitory effect on hepatic biosynthesis of cholesterol at the mevalonate step.28 Hypercholesterolemia is associated with endothelial dysfunction,13 29 which can predispose the circulation to coronary artery disease. Several animal and human studies30 31 indicate improved endothelial function associated with a lowering of serum cholesterol. The statins exert beneficial effects in coronary artery6 and cerebrovascular32 disease states, including reducing overall mortality3 and improving endothelial function in hypercholesterolemic states.33 Recently, the statins have been reported to promote endothelial function in the absence of hypercholesterolemia in isolated endothelial cells,34 in isolated perfused rat hearts,10 and in intact organisms.7 35 Because of the important role exerted by NO in attenuating leukocyte-endothelium interactions during inflammatory states,14 24 our study was designed to investigate the effects and mechanisms of a statin on leukocyte–endothelial cell interaction in vivo in normocholesterolemic, intact animals.
The present study clearly demonstrates that simvastatin, given 18 hours before examination, is able to attenuate both L-NAME– and thrombin-induced leukocyte–endothelial cell interactions via a P-selectin–dependent mechanism. In addition, these effects of simvastatin were not related to any alteration of the animals’ normal plasma cholesterol levels. We have previously demonstrated that simvastatin downregulates CD18 on stimulated polymorphonuclear cells in normocholesterolemic rats.10 These antiadherence effects are not mediated by simvastatin’s cholesterol-lowering effects and clearly point toward other effects of HMG-CoA reductase inhibitors. Moreover, these effects occurred without any significant systemic hemodynamic or local microvascular changes in mean arterial blood pressure or venular shear rates.
Leukocyte rolling, adherence, and subsequent transmigration through the
endothelial wall of the mesenteric microcirculation are
key steps in the inflammatory response brought about by
pathophysiological states (eg, trauma,
ischemia-reperfusion, and shock).14 Leukocyte
rolling is mediated by the selectin family of adhesion molecules. The
selectins bind to sialylated carbohydrate determinants related to
sialyl Lewisx.36 One important
adhesion molecule involved in early
leukocyte-endothelium interaction is P-selectin.
P-selectin binds to sialylated carbohydrate determinants, especially to
its high-affinity ligand, P-selectin glycoprotein ligand-1,
which is located on the microvilli of leukocytes.37 Thus,
P-selectin glycoprotein ligand-1 is favorably positioned to
interact with its counterligands under flow
conditions.38 39 P-selectin is stored in the 
-granules
of platelets and in Weibel-Palade bodies of
endothelial cells. It is rapidly translocated to
platelet and endothelial cell surfaces in response
to various inflammatory stimuli, including thrombin, histamine, and
oxygen-derived free radicals.19 21 In this manner,
selectins initiate rolling and tethering of circulating leukocytes to
the endothelial cell surface.40 At
physiological flow rates, these inflammatory
stimuli promote leukocyte recruitment to the local microvasculature and
provide the basis of activation-induced adhesion strengthening through
the ß2-integrins (CD11/CD18). These
surface-associated glycoproteins possess a common ß-chain
(CD18) and 1 of the 3 separate -chains (CD11a, CD11b, or
CD11c).41 It has been previously shown that
lovastatin decreases CD11b expression and CD11b-dependent
adhesion of monocytes to the endothelium in humans,
independent of any cholesterol-lowering
effects.42 This phenomenon could contribute to the
observed endothelium-protective effects in the
present study, independent of the well-known lipid-lowering effects
of the HMG-CoA reductase inhibitors. Once firmly adhered
through the interaction of the ß2-integrins
with their endothelial counterreceptor, intercellular
adhesion molecule-1, leukocytes can then undergo further activation,
migrate across the endothelium, and release free
radicals and proteolytic enzymes with subsequent tissue
injury.23 43 44 It is possible that platelets may
interact with leukocytes via platelet P-selectin/leukocyte
P-selectin glycoprotein ligand-1 binding. However, under
the conditions of our experiments, we did not observe any such
interaction, either during intravital microscopy or by
immunohistochemistry.
The importance of leukocytes in mediating inflammatory injury has been confirmed by the fact that neutrophil depletion or administration of antibodies directed against specific cell-adhesion molecules exerts a beneficial effect during ischemia-reperfusion, trauma, and shock.45 46 47 An important early event during these conditions is endothelial dysfunction, which is characterized by reduced synthesis and release of NO,48 an important endothelium-derived substance involved in the inhibition of platelet aggregation,16 attenuation of neutrophil adherence,17 and reduction in microvascular permeability.49 Moreover, Davenpeck et al24 demonstrated that reduced endogenous NO synthesis results in the upregulation of P-selectin on the endothelial cell surface of mesenteric microvessels. Loss of NO thus results in enhanced leukocyte-endothelium interaction, and replacement of the reduced NO attenuates these interactions.50
In this study, the degree of leukocyte rolling, adhesion, and transmigration after acute endothelial dysfunction was determined in response to 2 rapid-onset stimuli in vivo under normal hemodynamic conditions. Activation of the rat mesenteric endothelium with effective stimulatory concentrations of L-NAME (50 µmol/L) or thrombin (0.5 U/mL) significantly increased leukocyte rolling, adherence, and transmigration. First, we demonstrated that the inflammatory effects occurring after acute inhibition of NO synthase and the subsequent decrease in NO release with L-NAME could be significantly inhibited by pretreatment with simvastatin. This beneficial effect on leukocyte-endothelium interaction is probably mediated in part by stimulating basal NO release and the subsequent diminished P-selectin expression in the L-NAME–superfused mesentery, since we could demonstrate significantly reduced levels of P-selectin expression on postcapillary venules in the simvastatin-treated group. In support of this view, NO donors are known to prevent both leukocyte rolling and adherence and endothelial cell surface expression of adhesion molecules.22 50 In addition, Laufs et al34 recently demonstrated upregulation of endothelial NO synthase by HMG-CoA reductase inhibitors via posttranscriptional mechanisms. Simvastatin was also shown to overcome the hypoxia-mediated inhibition of NO synthase activity.9 Furthermore, Endres et al51 demonstrated that prophylactic treatment with an HMG-Co-A reductase inhibitor reduced cerebral infarct size and improved neurological function after stroke in normocholesterolemic mice. The mechanisms of these cerebroprotective effects were related to an augmented cerebral blood flow but also appeared to be due to other known NO-mediated effects, such as inhibition of platelet aggregation or leukocyte adhesion.
In conclusion, this is the first study to demonstrate in vivo that administration of simvastatin, an HMG-CoA reductase inhibitor, inhibits leukocyte rolling, adherence, and transmigration in acute inflammatory states. This effect was found to be mediated by downregulation of P-selectin expression on endothelial cells and is also consistent with the downregulation of CD18 on stimulated polymorphonuclear cells. HMG-CoA reductase inhibitors may therefore have important anti-inflammatory effects besides their well-known lipid-lowering actions in hypercholesterolemic states. These newly observed effects may represent a new strategy for the primary prevention of tissue damage mediated by ischemia and reperfusion or similar inflammatory states.
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Acknowledgments |
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This work was supported in part by research grant No. GM-45434 (to A.M.L.) from the National Institutes of General Medical Sciences of the National Institutes of Health, Bethesda, Md. We thank Robert Craig for his expert technical assistance with the immunohistochemical procedures used in this study.
Received March 26, 1999; accepted June 14, 1999.
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