© 1997 American Heart Association, Inc.
Articles |
Effects of Fluvastatin on Leukocyte–Endothelial Cell Adhesion in Hypercholesterolemic Rats
From the Department of Physiology, Louisiana State University Medical Center, Shreveport.
Correspondence to D. Neil Granger, PhD, Department of Physiology and Biophysics, Louisiana State University Medical Center, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 71130-3932. E-mail dgrang{at}lsumc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract The overall objective of this study was to determine whether peroral treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin influences the leukocyte–endothelial cell adhesion (LECA) observed in postcapillary venules of hypercholesterolemic rats. Rats were fed either normal chow or a chow supplemented with 1% cholesterol for 10 days. Leukocyte adherence and extravasation, leukocyte rolling velocity, red blood cell velocity, and vessel diameter were monitored in mesenteric venules superfused with either 100 nmol/L platelet-activating factor (PAF) or 20 nmol/L leukotriene B4 (LTB4). Hypercholesterolemic rats exhibited an exaggerated LECA response compared with their normocholesterolemic counterparts. In hypercholesterolemic rats, treatment with fluvastatin significantly attenuated the leukocyte-adherence responses to PAF and LTB4 as well as the leukocyte emigration response to LTB4. Fluvastatin treatment also inhibited the PAF- and LTB4-induced reductions in leukocyte rolling velocity. These findings indicate that fluvastatin blunts the inflammatory responses elicited in postcapillary venules by lipid mediators.
Key Words: inflammation • postcapillary venules • atherosclerosis • leukocyte adherence
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Atherogenesis is a complex disease process that is associated with endothelial cell dysfunction and/or injury in both large and microscopic blood vessels.1 2 There is a growing body of evidence that invokes a role for leukocyte–endothelial cell interactions in the pathobiology of atherosclerosis. Indeed, the adherence of circulating monocytes and lymphocytes to the endothelial lining of large arteries is one of the earliest detectable events in human1 and experimental atherosclerosis.1 3 4 5 It has been proposed that the subsequent transendothelial migration of these adherent leukocytes and their accumulation in the intima and transformation into lipid-engorged "foam cells" results in the formation of atherosclerotic plaques.1 A role for endothelial cells in the initiation of this process is supported by numerous reports of an increased expression of adhesion molecules on endothelial cells of atherosclerotic vessels.6
Several experimental strategies have been employed to simulate the leukocyte–endothelial cell interactions of atherosclerosis in experimental animals, including intravascular administration of oxidized LDLs7 and placement of animals on high-cholesterol diets.8 It has been shown that isolated rabbit coronary arteries9 and intact rat mesenteric venules10 sustain a higher level of neutrophil–endothelial cell adhesion in hypercholesterolemic animals compared with their normocholesterolemic counterparts. The results of these studies also suggest that the increased cell-to-cell adhesion results from an increased expression of adhesion molecules (eg, P-selectin and ICAM-1) on the surface of endothelial cells and that a decreased basal release of NO from endothelial cells accounts for the increased LECA.7 8 It was proposed that correction of the hypercholesterolemia-induced alteration in NO bioavailability with NO-donating compounds should prove effective in reducing the neutrophil adhesion and consequent dysfunction of large and small vessels that is associated with atherosclerosis.
Studies of neutrophil adherence to coronary artery endothelium in hypercholesterolemic animals have revealed that administration of the HMG-CoA reductase inhibitor lovastatin profoundly reduces the hyperadhesiveness of neutrophils that is normally observed in these vessels.7 Furthermore, the HMG-CoA reductase inhibitor attenuated the reduced basal NO production by endothelial cells in hypercholesterolemic coronary arteries, thereby supporting the view that an underlying cause of the increased leukocyte adhesion in hypercholesterolemia is an altered NO bioavailability.9 While these observations suggest that HMG-CoA reductase inhibitors are effective in blunting the inflammatory responses that occur in large blood vessels of animals placed on a high-cholesterol diet, it remains unclear whether these inhibitors exert a similar protective action on the LECA that occurs in postcapillary venules of hypercholesterolemic animals. Furthermore, it is not clear whether the beneficial action of an HMG-CoA reductase inhibitor on the exaggerated inflammatory responses observed in animals on a high-cholesterol diet is directly related to its ability to lower plasma cholesterol. Hence, the overall objective of the present study was to determine whether peroral treatment of hypercholesterolemic rats with fluvastatin (6 mg/kg for 10 days), an inhibitor of HMG-CoA reductase,11 alters the LECA elicited in postcapillary venules exposed to either PAF or LTB4.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Male Sprague-Dawley rats (125 to 149 g) were maintained on a purified laboratory diet. Rats were then separated into two treatment groups: a control group that received a standard laboratory diet and a cholesterol-fed group that received a 1% cholesterol-enriched diet (Oriental Kobo Co) supplemented with 0.2% cholic acid (which increases cholesterol absorption) and 2.5% olive oil as dietary fat for 10 days before the experiment. Some of the high-cholesterol–fed animals were perorally treated for 10 days with fluvastatin sodium (Sandoz Research Institute) or pravastatin sodium (another HMG-CoA reductase inhibitor extracted from tablets of Mevalotin by Sandoz Yakuhin) at a dose of 6 mg/kg once daily. In control animals, the same volume of distilled water was administered perorally.
Surgical Procedures
Rats were initially anesthetized with an
intraperitoneal injection of thiobutabarbital
(Research Biochemicals International) at a dose of 120 mg/kg
body weight, and a tracheotomy was performed to facilitate breathing.
The right carotid artery was cannulated and systemic
arterial pressure was measured with a pressure transducer
(Statham) connected to the carotid artery cannula. Systemic blood
pressure and heart rate were continuously recorded with a Grass
physiological recorder (Grass Instruments). A
middle abdominal incision was made, and a segment of the ileum was
exteriorized through the incision. All exposed tissue was moistened
with saline-soaked gauze to minimize evaporation and tissue
dehydration.
Intravital Videomicroscopy
Rats were placed in a right lateral recumbent position on an
adjustable Plexiglas acrylic plastic microscope stage and the mesentery
was prepared for microscopic observation as described
previously.12 The mesentery was draped over an optically
clear viewing glass that allowed for examination of a 2-cm2
segment of tissue. The temperature of the pedestal was maintained at
37°C with a constant temperature circulator (Fisher Scientific, model
80). Rectal temperature was monitored using an electrothermometer. The
exposed bowel wall and mesentery were covered with Saran Wrap (Dow
Chemical Co), and the mesentery was superfused with warmed
bicarbonate-buffered saline (pH 7.4) that was bubbled with a mixture of
5% CO2, 95% N2.
Venules were observed through an intravital videomicroscope (Leitz, Ortholux II). The mesentery was transilluminated, and a video camera (Hitachi, VK-C150) mounted on the microscope projected the image onto a color monitor (Sony, PVM-2030). The images were recorded with a videocassette recorder for playback analysis.
Single unbranched venules with diameters ranging between 25 and 35
µm were selected for study. Venular diameter (D) was measured by
using a video caliper (Microcirculation Research Institute), and red
blood cell centerline velocity was measured by using an optical
Doppler velocimeter (Microcirculation Research
Institute). Venular blood flow was calculated as the product of
mean red blood cell velocity (Vmean=centerline
velocity/1.6)13 and venular cross-sectional area (assuming
cylindrical geometry). The number of adherent leukocytes was determined
off-line during playback (10 minutes) of videotaped images. A leukocyte
was considered to be adherent to the venular
endothelium if it remained stationary for 
30
seconds.12 Adherent cells were determined as the number
per 100-µm length of venule for 10 minutes. The number of emigrated
leukocytes was determined off-line during playback of videotaped
images. Leukocytes that were clearly visible outside the venule were
counted as emigrated cells. Leukocyte emigration was expressed as the
change in the number per microscopic field (2.2x104
µm2). Rolling leukocytes were defined as white blood
cells that moved at a velocity less than that of red blood cells in the
same vessel. Leukocyte rolling velocity (VRL) was
determined as the time required for a leukocyte to transverse a given
length of venule. The flux of rolling leukocytes (FRL) was
determined as the number of cells rolling past a fixed point in the
vessel per minute. The number of rolling leukocytes within the vessel
at any given moment was determined by dividing FRL by
VRL.14 The venular wall shear rate (
) was
calculated by using the Newtonian definition,
=8(Vmean/D).15
Serum Total Cholesterol and Nitrate/Nitrite
Levels
A 0.5-mL blood sample was collected via the carotid artery.
Total serum cholesterol concentration was enzymatically
measured by using a commercial kit (Sigma Chemical Company).
Whole-animal NO production was assessed by measurements of
serum nitrite/nitrate concentration.16 Serum levels of
nitrite and nitrate were determined by a modification of the method of
Green et al.17 Briefly, 400 µL of water was added to 100
µL of plasma. Protein was precipitated by the addition of 25 µL
30% ZnSO4. Supernatants (500 µL) were incubated with
E coli, HEPES buffer (pH 7.4), and NH4 formate
(pH 7.4) for 60 minutes at 37°C to reduce nitrate to nitrite. Nitrite
was then quantified by using the Griess reagent (1% sulfanilamide,
0.1% naphthylethylenediamine dihydrochloride, and 2.5%
H3PO4) to a 500-µL supernatant of the sample.
Nitrite concentrations were calculated from a standard curve, using
sodium nitrite (Sigma) as the standard.
Experimental Protocols
After all parameters that were measured on-line
(arterial pressure, erythrocyte velocity, and venular
diameter) were in a steady state, images from the mesenteric
preparation were recorded on videotape for 10 minutes. If there
were 6 adherent leukocytes and/or 8 emigrated leukocytes over a
10-minute observation period under basal conditions, the experiment was
discarded. The mesentery was superfused with either 100 nmol/L
PAF (Sigma) or 20 nmol/L LTB4 (Calbiochem),
dissolved in bicarbonate-buffered saline, for 30 minutes, with video
recordings and repeat measurements of all
parameters made during the final 10 minutes of superfusion.
In control experiments, the same protocol was employed, except that
bicarbonate-buffered saline was used as the perfusate for the
entire procedure.
Statistical Analysis
All data were analyzed using standard statistical
analyses, ie, ANOVA with Scheffé's posthoc test. All
values are expressed as mean±SE, and statistical significance was set
at P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Table 1
summarizes the serum
cholesterol and nitrate/nitrite concentrations and systemic
blood pressure measured in rats placed on normal chow or a
high-cholesterol diet (10 days), with and without peroral
fluvastatin. Blood pressure did not differ among the three
experimental groups. Serum cholesterol level was more than
three times higher in rats placed on a high-cholesterol
diet. Fluvastatin treatment (6 mg ·
kg-1 · d-1 for
10 days) did not alter the serum cholesterol levels. While
there was a tendency for serum nitrate/nitrite levels to fall in
hypercholesterolemic rats, this response was not
statistically significant. Fluvastatin did not alter serum
nitrate/nitrite levels in hypercholesterolemic
rats.
|
Table 2 compares the basal values for
different inflammatory and microhemodynamic
variables in mesenteric venules of control and
hypercholesterolemic rats with and without
fluvastatin treatment. Although blood flow, mean
erythrocyte velocity, and wall shear rate did not differ among the
three groups, the number of adherent and rolling leukocytes, as well as
the flux of rolling leukocytes, was elevated, while leukocyte rolling
velocity was reduced in venules of hypercholesterolemic
animals compared with controls. The number of emigrated leukocytes did
not differ between the two groups. Fluvastatin treatment in
hypercholesterolemic rats reduced the number of
adherent leukocytes and restored leukocyte rolling velocity to normal.
In a preliminary study, it was shown that fluvastatin in a
single application of high concentration suppressed PAF- or
LTB4-stimulated (but not basal values of)
leukocyte–endothelial cell interactions, as seen in
the present study with chronic treatment.
|
In rats fed either normal chow or a high-cholesterol diet, superfusion of the mesentery with either PAF or LTB4 resulted in the recruitment of adherent, emigrated, and rolling leukocytes, while not altering venular hemodynamics (blood flow, shear rate, and red blood cell velocity). Although both inflammatory mediators tended to elicit larger inflammatory responses (recruitment of adherent, emigrated, and rolling leukocytes) in venules of hypercholesterolemic (versus control) animals, these differences were not statistically significant.
Fig 1 illustrates that the recruitment of
firmly adherent leukocytes elicited by either PAF or LTB4
in hypercholesterolemic rats was significantly
attenuated by treatment with fluvastatin. Figs 2 and 3
demonstrate that the recruitment of emigrated leukocytes and the
reduction of leukocyte rolling velocity induced by either PAF or
LTB4 were blunted in hypercholesterolemic
rats treated with fluvastatin. Although a trend exists,
fluvastatin did not have a significant effect on
PAF-induced emigration. The protective actions of
fluvastatin on leukocyte recruitment in
hypercholesterolemic rats was not accompanied by
changes in venular hemodynamics, ie, venular blood
flow, red blood cell velocity, and shear rate were unaffected by
fluvastatin.
|
P<.05 vs PAF or
LTB4.
|
|
Table 3 illustrates that
pravastatin, another HMG-CoA reductase
inhibitor, did not affect the recruitment of adherent and
emigrated leukocytes and the reduction in leukocyte rolling velocity
normally elicited by PAF and LTB4.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
There is a growing body of evidence that implicates leukocytes in the abnormal vascular function associated with hypercholesterolemia9 10 and atherogenesis.7 While much emphasis has been given to the role of monocytes in the initiation and development of atherosclerotic lesions,1 3 4 5 recent studies have described an accelerated recruitment of granulocytes to the endothelial cell surface of large and small blood vessels in the early stages of experimental hypercholesterolemia.10 Furthermore, it has been demonstrated that interventions (eg, monoclonal antibodies against leukocyte adhesion molecules or NO donors) that interfere with the recruitment of leukocytes help to maintain vessel function and endothelial barrier integrity in hypercholesterolemic blood vessels.10 The results of the present study provide support for a beneficial action of the HMG-CoA reductase inhibitor fluvastatin in blunting the recruitment of leukocytes into lipid mediator–stimulated postcapillary venules of hypercholesterolemic rats. Our data also indicate that the protective action of this agent is independent of the serum cholesterol–lowering effect observed after prolonged treatment in other species. Hence, our findings suggest that fluvastatin therapy may represent a novel approach for the prevention or attenuation of the leukocyte–endothelial cell interactions that appear to contribute to the development of atherosclerosis.
As a species, rats (eg, compared with hamsters) are known to be tolerant to the lipid-lowering effects of HMG-CoA reductase inhibitors. The expected clinical dose of fluvastatin is 0.5 to 1.0 mg/kg, which is 6 to 12 times lower than the dosage used to inhibit LECA in our study. However, previous reports on pravastatin actions in WHHL rabbits have employed doses as high as 50 mg/kg.18 While we cannot exclude a nonspecific action of the 6-mg/kg dose of fluvastatin, the lack of effect of this dose on basal LECA and venular hemodynamics would argue against significant nonspecific actions of this concentration in rats.
The results of the present study indicate that placement of rats on
a high-cholesterol diet for a period of days results in a
threefold increase in serum cholesterol levels, with an
accompanying recruitment of rolling and emigrated leukocytes in
unstimulated mesenteric venules (Tables 1
and 2). These observations
are consistent with the findings of a recent report by Gauthier
and associates10 wherein it was shown that rats placed on
a high-cholesterol diet for 2 weeks exhibit a marked
increase in the percentage of postcapillary venules that express the
endothelial cell adhesion molecules P-selectin and
ICAM-1. P-Selectin expression on endothelial cells is
generally associated with an increased recruitment of rolling
leukocytes, while ICAM-1 expression favors the emigration of leukocytes
across microvascular endothelium.19
In addition to the inhibitory effects of fluvastatin on LECA in inflamed venules, chronic treatment of hypercholesterolemic rats with fluvastatin lowered the basal level of adherent leukocytes, with an improved leukocyte rolling velocity. Inasmuch as fluvastatin does not alter basal leukocyte adhesion in normocholesterolemic (on normal chow) rats (unpublished observations), it may be proposed that the actions of this agent are related to plasma cholesterol levels. However, this possibility seems unlikely, since no changes in serum cholesterol and lipids were observed in hypercholesterolemic rats treated with fluvastatin. In a recent study, it was demonstrated that serum lipid peroxides in hypercholesterolemic rabbits were markedly reduced by fluvastatin.20 These observations suggest that the beneficial action of fluvastatin on leukocyte adhesion may be related to a corresponding antioxidant effect of the drug.
The mechanism(s) that underlies the enhanced recruitment of rolling leukocytes in hypercholesterolemic microvessels has not been defined. A diminished capacity of endothelial cells to produce NO has been invoked to explain the altered endothelium-dependent vasorelaxation observed in hypercholesterolemic microvessels.20 Inasmuch as inhibition of NO synthase activity in postcapillary venules promotes the recruitment of leukocytes and causes a corresponding increase in the expression of P-selectin,21 it is conceivable that a reduced bioavailability of NO accounts for the inflammatory responses that we observed in unstimulated venules of hypercholesterolemic rats. The tendency for serum nitrate/nitrite levels to fall in our hypercholesterolemic rats supports this possibility.
An interesting and important observation in our study is that orally administered fluvastatin significantly attenuates the leukocyte adherence and consequent emigration across venules that is elicited by PAF in hypercholesterolemic rats. Fluvastatin treatment also blunted the LECA interactions that result from superfusion of mesenteric venules of hypercholesterolemic animals with LTB4. The ability of fluvastatin to interfere with both PAF- and LTB4-induced inflammatory responses suggests that the HMG-CoA reductase inhibitor does not exert its inhibitory action by interacting with a specific receptor. Other potential mechanisms of action of fluvastatin that appear unlikely, on the basis of our data, are a serum cholesterol–lowering effect and/or an improvement of venular perfusion. It has previously been shown that rat serum cholesterol levels are unresponsive to the cholesterol-lowering effect of HMG-CoA reductase inhibitors.22
There are three possible modes of action of fluvastatin that could account for its antiinflammatory effects in hypercholesterolemic venules: (1) inhibition of leukocyte and/or endothelial cell adhesion molecule expression, (2) attenuation of oxygen radical formation and the resultant lipid peroxidation, and (3) prevention of formation of a proinflammatory product of cholesterol metabolism (eg, mevalonic acid). The results of a preliminary in vitro study indicate that fluvastatin acts on a human monocyte cell line (U937) to suppress the expression of lymphocyte-function associated antigen-1, without affecting the expression of ICAM-1 and vascular adhesion molecule-1, on cultured human endothelial cells. Since antioxidants such as probucol have been shown to slow the progression of atherosclerotic lesion formation in hypercholesterolemic animals24 and because lipid peroxidation products can promote LECA,25 it is possible that fluvastatin acts to attenuate the enhanced peroxidation of lipoproteins and cell membranes that accompanies high serum cholesterol levels. In the present study, fluvastatin treatment attenuated PAF- and LTB4-induced LECA, but pravastatin treatment did not. It has been demonstrated that fluvastatin and pravastatin exert different effects on smooth muscle proliferation. Fluvastatin inhibits the proliferation of vascular smooth muscle cells in vitro26 and in vivo,27 but pravastatin does not. Furthermore, fluvastatin has been shown to inhibit intimal thickening after catheterization-induced injury, an effect that has been attributed to reduced migration and proliferation of smooth muscle cells rather than a serum lipid-lowering action. Pravastatin did not show the same inhibitory effects.28 Thus, it appears unlikely that the difference in the antiatherosclerotic effect of the two enzyme inhibitors can be explained in terms of lipid-lowering effectiveness. Pravastatin inhibits HMG-CoA reductase in the liver to a greater extent than in other organs, and it readily permeates hepatocytes.29 If fluvastatin, with a greater lipophilicity than pravastatin, is more permeable to smooth muscle membranes, then this factor may explain the differential antiatherosclerotic effects of the two HMG-CoA reductase inhibitors. Finally, mevalonate has been shown to reverse some of the biological actions of HMG-CoA reductase inhibitors, particularly processes linked to cell growth.30 Hence, the chronic reduction of cellular mevalonate that is expected with prolonged treatment with an HMG-CoA reductase inhibitor may exert an action on the leukocyte and endothelial cell surface that limits their ability to adhere.
In conclusion, our findings indicate that hypercholesterolemia enhances the adhesive interaction between leukocytes and endothelial cells in postcapillary venules. The HMG-CoA reductase inhibitor fluvastatin significantly reduces the inflammatory responses elicited in venules of hypercholesterolemic rats by the lipid mediators PAF and LTB4. These observations suggest that fluvastatin may slow or prevent the initiation and progression of atherosclerosis-associated vascular dysfunction by inhibiting inflammatory cell–endothelial cell interactions.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by a grant from the Heart, Lung, and Blood Institute (HL 26441).
Received April 12, 1996; accepted November 5, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;314:488-500.[Medline] [Order article via Infotrieve]
2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809.[Medline] [Order article via Infotrieve]
3.
Davies MJ, Woolf N, Rowles PM, Pepper J.
Morphology of the endothelium over atherosclerotic
plaques in human coronary arteries. Br Heart
J. 1988;60:459-464.
4.
Hansson GK, Jonasson L, Seifert PS, Stemme S.
Immune mechanisms in atherosclerosis.
Arteriosclerosis. 1989;9:567-578.
5. Munro JM, Cotran RS. Biology of disease: the pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest. 1988;58:249-261.[Medline] [Order article via Infotrieve]
6. Wissler RW. Progression and regression of atherosclerotic lesions. Adv Exp Med Biol. 1978;104:77-109.[Medline] [Order article via Infotrieve]
7.
Lehr HA, Seemüller J, Hübner C, Menger MD,
Messmer K. Oxidized LDL-induced
leukocyte/endothelium interaction in vivo involves the
receptor for platelet-activating factor. Arterioscler
Thromb. 1993;13:1013-1018.
8.
Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke
JP. Enhanced endothelial adhesiveness in
hypercholesterolemia is attenuated by
L-arginine. Circulation. 1994;89:2176-2182.
9.
Lefer AM, Ma X. Decreased basal nitric oxide
release in hypercholesterolemia increases
neutrophil adherence to rabbit coronary artery
endothelium. Arterioscler Thromb. 1993;13:771-776.
10.
Gauthier TW, Scalia R, Murohara T, Guo J, Lefer
AM. Nitric oxide protects against
leukocyte-endothelium interactions in the early stages
of hypercholesterolemia.
Arterioscler Thromb Vasc Biol. 1995;15:1652-1659.
11. Hayashi K, Kurokawa J, Nomura S, Kuga Y, Ohkura Y, Kajiyama G. Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cell. Biochim Biophys Acta. 1993;1167:223-225.[Medline] [Order article via Infotrieve]
12.
Granger DN, Benoit JN, Suzuki M, Grisham MB.
Leukocyte adherence to venular endothelium during
ischemia-reperfusion. Am J Physiol. 1989;257:G704-G708.
13. Davis MJ. Determination of volumetric flow in capillary tubes using an optical Doppler velocimeter. Microvasc Res. 1987;34:223-230.[Medline] [Order article via Infotrieve]
14. Granger DN, Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol. 1994;55:662-675.[Abstract]
15. House SD, Lipowsky HH. Leukocyte-endothelium adhesion: microhemodynamics in mesentery of the cat. Microvasc Res. 1987;34:363-379.[Medline] [Order article via Infotrieve]
16. Yamada T, Sartor RB, Marshall S, Specian RD, Grisham MB. Mucosal injury and inflammation in a model of chronic granulomatous colitis in rats. Gastroenterology. 1993;104:759-771.[Medline] [Order article via Infotrieve]
17. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1982;126:131-138.[Medline] [Order article via Infotrieve]
18. Tsujita Y, Kuroda M, Shimada Y, Tanzawa K, Arai M, Kaneko I, Tanaka M, Masuda H, Tarumi C, Watanabe Y, Fujii S. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biophys Acta. 1986;877:50-60.[Medline] [Order article via Infotrieve]
19.
Zimmerman BJ, Holt JW, Paulson JC, Anderson DC,
Miyasaka M, Tamatani T, Todd RF, Rusche JR, Granger DN.
Molecular determinants of lipid mediator–induced leukocyte adherence
and emigration in rat mesenteric venules. Am J
Physiol. 1994;266:H847-H853.
20. Mitani H, Bandoh T, Ishikawa J, Kimura M, Totsuka T, Hayashi S. Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. Br J Pharmacol. 1996;119:1269-1275.[Medline] [Order article via Infotrieve]
21.
Quyyumi AA, Dakak N, Andrews NP, Gilligan DM, Panza JA,
Cannon RO. Contribution of nitric oxide to metabolic
coronary vasodilation in the human heart.
Circulation. 1995;92:320-326.
22. Davenpeck KL, Gauthier TW, Lefer AM. Inhibition of endothe- lial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology. 1994;107:1199-1201.[Medline] [Order article via Infotrieve]
23. Endo A, Tsujita Y, Kuroda M, Tanzawa K. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Acta. 1979;575:266-276.[Medline] [Order article via Infotrieve]
24.
Carew TE, Schwenke DC, Steinberg D.
Antiatherogenic effect of probucol unrelated to its
hypocholesterolemic effect: evidence that antioxidants
in vivo can selectively inhibit low density lipoprotein degradation in
macrophage-rich fatty streaks and slow the progression of
atherosclerosis in the Watanabe heritable
hyperlipidemic rabbit. Proc Natl Acad Sci
U S A. 1987;84:7725-7729.
25.
Liao L, Aw TY, Kvietys RR, Granger DN. Oxidized
LDL–induced microvascular dysfunction: dependence on oxidation
procedure. Arterioscler Thromb Vasc Biol. 1995;15:2305-2311.
26. Corsini A, Mazzotti M, Raiteri M, Soma MR, Gabbiani G, Fumagalli R, Paoletti R. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis. 1993;101:117-125.[Medline] [Order article via Infotrieve]
27.
Soma MR, Donetti E, Parolini C, Mazzini G, Ferrai C,
Fumagalli R, Paoletti R. HMG-CoA reductase
inhibitors: in vivo effects on carotid intimal thickening
in normocholesterolemic rabbits.
Arterioscler Thromb. 1993;13:571-578.
28. Bandoh T, Mitani H, Niihashi M, Kusumi Y, Ishikawa J, Kimura M, Totsuka T, Sakurai I, Hayashi S. Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery. Eur J Pharmacol. 1996;315:37-42.[Medline] [Order article via Infotrieve]
29.
Scott WA. Hydrophilicity and the differential
pharmacology of pravastatin. In: Wood C, ed.
Lipid Management: Pravastatin and the Differential
Pharmacology of HMG-CoA Reductase Inhibitors. London,
UK: Royal Society of Medical Services; 1989;16:17. London Round Table
Series.
30. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425-430.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  P. M. Winter, S. D. Caruthers, H. Zhang, T. A. Williams, S. A. Wickline, and G. M. Lanza Antiangiogenic synergism of integrin-targeted fumagillin nanoparticles and atorvastatin in atherosclerosis. J. Am. Coll. Cardiol. Img., September 1, 2008; 1(5): 624 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Keddissi, W. G. Younis, E. A. Chbeir, N. N. Daher, T. A. Dernaika, and G. T. Kinasewitz The Use of Statins and Lung Function in Current and Former Smokers Chest, December 1, 2007; 132(6): 1764 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamada, E. Sakurai, M. Itaya, S. Yamasaki, and Y. Ogura Inhibition of Laser-Induced Choroidal Neovascularization by Atorvastatin by Downregulation of Monocyte Chemotactic Protein-1 Synthesis in Mice Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1839 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Fessler, S. K. Young, S. Jeyaseelan, J. G. Lieber, P. G. Arndt, J. A. Nick, and G. S. Worthen A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 606 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
J. Han, X. Zhou, T. Yokoyama, D. P. Hajjar, A. M. Gotto Jr, and A. C. Nicholson Pitavastatin Downregulates Expression of the Macrophage Type B Scavenger Receptor, CD36 Circulation, February 17, 2004; 109(6): 790 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. H. Han, Y. Chen, M. K. Chang, Y. C. Han, J.-H. Park, S. R. Green, A. Boullier, and O. Quehenberger LDL activates signaling pathways leading to an increase in cytosolic free calcium and stimulation of CD11b expression in monocytes J. Lipid Res., July 1, 2003; 44(7): 1332 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
|
|
|
|
|
|
C. Stefanadis, K. Toutouzas, M. Vavuranakis, E. Tsiamis, D. Tousoulis, D.B. Panagiotakos, S. Vaina, C. Pitsavos, and P. Toutouzas Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques Eur. Heart J., November 1, 2002; 23(21): 1664 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]
|
|
|
|
|
|
M. Yoshida, T. Sawada, H. Ishii, R. E. Gerszten, A. Rosenzweig, M. A. Gimbrone Jr, Y. Yasukochi, and F. Numano HMG-CoA Reductase Inhibitor Modulates Monocyte-Endothelial Cell Interaction Under Physiological Flow Conditions In Vitro : Involvement of Rho GTPase-Dependent Mechanism Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1165 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Lefer, R. Scalia, and D. J Lefer Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease Cardiovasc Res, February 1, 2001; 49(2): 281 - 287. [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability Cardiovasc Res, September 1, 2000; 47(4): 648 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Corsini Reviews: Fluvastatin: Effects Beyond Cholesterol Lowering Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(3): 161 - 175. [Abstract] [PDF]
|
|
|
|
|
|
D. Pruefer, R. Scalia, and A. M. Lefer Simvastatin Inhibits Leukocyte-Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2894 - 2900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, P. Moesner, N. L. Kovach, R. Bailey, A. D. Hamilton, S. M. Sebti, and J. M. Harlan Integrin-dependent Leukocyte Adhesion Involves Geranylgeranylated Protein(s) J. Biol. Chem., November 19, 1999; 274(47): 33334 - 33340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Vaughan and N. Delanty Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke Stroke, September 1, 1999; 30(9): 1969 - 1973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Han, K. O. Han, S. R. Green, and O. Quehenberger Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia: differential effects of plasma lipoproteins on monocyte function J. Lipid Res., June 1, 1999; 40(6): 1053 - 1063. [Abstract] [Full Text]
|
|
|
|
|
|
N. Mori, Y. Horie, M. E. Gerritsen, and D. N. Granger Ischemia-reperfusion induced microvascular responses in LDL-receptor -/- mice Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1647 - H1654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Rabbani and E. J. Topol Strategies to achieve coronary arterial plaque stabilization Cardiovasc Res, February 1, 1999; 41(2): 402 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Han, R. K. Tangirala, S. R. Green, and O. Quehenberger Chemokine Receptor CCR2 Expression and Monocyte Chemoattractant Protein-1–Mediated Chemotaxis in Human Monocytes : A Regulatory Role for Plasma LDL Arterioscler Thromb Vasc Biol, December 1, 1998; 18(12): 1983 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kurose, R. E. Wolf, M. B. Grisham, and D. N. Granger Hypercholesterolemia Enhances Oxidant Production in Mesenteric Venules Exposed to Ischemia/Reperfusion Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1583 - 1588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Rosenson and C. C. Tangney Antiatherothrombotic Properties of Statins: Implications for Cardiovascular Event Reduction JAMA, May 27, 1998; 279(20): 1643 - 1650. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||