Unraveling Pleiotropic Effects of Statins on Plaque Rupture
Wulf Palinski and Claudio Napoli
Arterioscler Thromb Vasc Biol. 2002;22:1745-1750
doi: 10.1161/01.ATV.0000038754.39483.CD
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Editorial
Unraveling Pleiotropic Effects of Statins on Plaque Rupture
Wulf Palinski, Claudio Napoli
S
everal large-scale clinical trials have conclusively
shown that statins markedly reduce clinical endpoints
of atherosclerosis.1 A plethora of studies has also
reported effects of statins other than cholesterol-lowering.2
These include effects on endothelial function, such as NO
generation and NO-mediated vascular relaxation, the recruitment of monocytes and T cells into the arterial intima, their
subsequent activation and expression of proinflammatory
factors, the proliferation of vascular smooth muscle cells
(VSMCs), and other events that result in arterial remodeling
(Table). However, to date only a minority of these “pleiotropic” effects of statins have been demonstrated to be truly
cholesterol-independent, ie, reversible by geranylgeranylpyrophosphate (GGPP), but not by cholesterol. (GGPP and
cholesterol represent separate branches of the mevanolate
pathway downstream of the step blocked by HMG-CoA
reductase inhibitors.) For example, the elegant work of Liao
and colleagues3 established that the modulation of NO is due
to the inhibition of GGPP that in turn affects the bioavailability of regulatory proteins, such as Ras and Rho. It has also
been established that statins may inhibit atherogenesis by
reducing the formation of superoxide and other oxygen
radicals that modulate many intracellular signaling pathways.4 Finally, statins may affect the consequences of plaque
rupture by modulating thrombosis and fibrinolysis. In fact,
statins decrease the expression of tissue factor in lesions,
reduce platelet activation, and improve fibrinolytic activity
through preservation of endothelial function, but it is unclear
whether these effects are common to the entire class of
statins, because some compounds seem to exert opposite
effects.5 Despite the increasing evidence obtained in vitro and
in experimental models, the clinical relevance of pleiotropic
effects of statins is still debated.6
See page 1832
The question whether specific pleiotropic effects contribute to the overall clinical benefits of statins is not an academic
one. Although neither the indication of statins for atherosclerosis-related diseases nor their dosage recommendations will
be affected by the answer, both an expansion of their
indication and the development of statin-analogues optimized
for specific pleiotropic effects can be envisaged, if it can be
shown that cholesterol-independent effects occur in vivo and
From the Department of Medicine, University of California, San
Diego, La Jolla.
Correspondence to Wulf Palinski, MD, Claudio Napoli MD, Department of Medicine, 0682, University of California San Diego, 9500
Gilman Dr, MTF 110, La Jolla, CA 92093-0682. E-mail
[email protected] [email protected]
(Arterioscler Thromb Vasc Biol. 2002;22:1745-1750.)
© 2002 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
DOI: 10.1161/01.ATV.0000038754.39483.CD
reduce disease severity or manifestation. For example, the
observation of anti-inflammatory effects and T cell–inhibition in vitro and the reduction of graft atherosclerosis and
mortality after heart transplantation have raised the hope that
statins could be indicated for a number of immune diseases
associated with chronic inflammation even under normocholesterolemic conditions.7 Compounds optimized for the competitive inhibition of the leukocyte function antigen 1 (LF-1)
have also been developed.8 In addition to prompting the
development of statin analogues, evidence for a biological
role of specific mechanisms may also provide an antiatherogenic indication for other, unrelated drugs targeting the same
mechanism, eg, NO donors.9
Unfortunately, neither in vitro experiments nor clinical
trials are likely to establish the impact of selective pleiotropic
effects of statins on atherogenesis or its clinical sequelae. Cell
culture experiments do not reflect the complex interactions
between the arterial wall and circulating leukocytes, platelets,
and elements of the plasmatic coagulation system, nor can
they mimic the influence of multiple organ systems that
govern lipid metabolism, immune responses, or regulation of
blood pressure. The main difficulty in the interpretation
of clinical trials is the powerful cholesterol-lowering effect of
statins, because genuine pleiotropic effects and cholesteroldependent ones frequently affect the same pathogenic mechanisms.7 Experimental models in which genetic, dietary, and
other variables can be tightly controlled provide the only
ethically acceptable way to determine the impact of selective
pleiotropic effects, even though few of these models are truly
representative of human pathology. The limitations imposed
by imperfect animal models are even greater when it comes to
assessing pleiotropic effects of statins on plaque vulnerability, plaque rupture, and atherothrombotic events.
In this issue of Arteriosclerosis, Thrombosis, and Vascular
Biology, Bea and colleagues10 report that simvastatin promotes plaque stability in apolipoprotein E– deficient
(apoE⫺/⫺) mice, independently of cholesterol lowering. In this
model, cholesterol-lowering effects can be presumed minimal, because hypercholesterolemia is primarily due to increases in chylomicron remnants and VLDL, which cannot be
cleared by hepatic LDL receptors or LRP via high-affinity
binding to apoE. The absence of significant cholesterollowering by statins in this model has been experimentally
validated before and used to demonstrate cholesterolindependent anti-inflammatory effects of simvastatin.11 Surprisingly, in the present longitudinal experiment spanning a
much longer period (24 weeks), a significant temporary
increase in plasma cholesterol was observed, the reason for
which remains unknown. Although the extent of atherosclerosis increased over time in both groups and the higher
plasma cholesterol level in the treatment group was associated with a consistent trend toward larger lesions, the fre-
1745
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1746
Arterioscler Thromb Vasc Biol.
November 2002
Pleiotropic Effect of Statins Potentially Affecting Plaque Rupture: Current Evidence for Their In Vivo Occurrence
Cholesterol Independent?
Effect of Statins on
In Vitro
In Vivo
Species
Endothelial function / vasotonus
Inhibition of endothelin 1 expression36
Yes
Increased expression and activity of endothelial nitric oxide (NO) synthase37,38
Yes
Stroke protection mediated by endothelial NO synthase39
Yes
Yes
Mouse
Preserved coronary endothelial function and coronary adventitial vasa vasorum40,41
Yes
Pig
Preserves myocardial perfusion and coronary microvascular permeability42
Yes
Pig
Macrophage and T cell recruitment / modulation of immune functions
Decreased leukocyte-endothelial interactions43
Yes
Rat
Decreased CD11b expression and CD11b-dependent endothelial adhesion of human monocytes44
Yes
No
Human
Inhibition of endothelial cell and monocyte MCP-1 synthesis and leukocyte recruitment into air pouch45
Yes
Yes
Mouse
Decreased integrin-dependent leukocyte adhesion46
Yes
Yes
Mouse
Inhibition of T cell activation through inhibition of MHC-II expression on APCs47
Inhibition of leukocyte adhesion, T cell stimulation, and peritoneal inflammation by inhibition of LF-1 (CD11a/CD18)48
?
Yes
Proinflammatory factors
Inhibition of natural killer cell cytotoxicity by compactin49
Yes
Inhibition of macrophage NO synthase and cytokines TNF␣, IL-1␤, IL-650
Yes
51
Inhibition of human B-lymphocyte activation
?
Reduced neointimal inflammation52
No
Rabbit
Anti-inflammatory and anti-atherosclerotic effects11
Yes
Mouse
No
Rabbit
Reduction of IL-1␤, IL-6, COX-2, and PPAR␣ mRNA in endothelial cells53
Reduced IL-6 synthesis in VSMCs54
?
Yes
Reduced MMP-9 secretion by macrophages55
?
Suppression of growth of macrophages expressing matrix metalloproteinases and tissue factor56
?
SMC proliferation / apoptosis of arterial cells / remodeling of the arterial wall
Decreased VSMC proliferation57
Yes
Increased apoptosis of VSMCs58
Yes
Increased SMC and collagen, and decreased metalloproteinases in atheroma59
No
Rabbit
?
Rabbit
No
Human
Yes
Rat/Mouse
No
Rat
Yes†
Rat
Yes
Mouse
Yes
Rabbit
No
Rabbit
Clinical outcomes not entirely explained by cholesterol-lowering (reduction of strokes, protective effects at ⬘normal⬘
cholesterol levels, etc)73–76
No
Human
Improvement of clinical outcomes after relatively short treatment period77,78
No
Human
Reduced graft atherosclerosis and mortality after heart transplantation79,80
No
Human
Reduced death after percutaneous coronary intervention81
No
Human
Modulation of angiogenesis60,61*
?
Decreased metalloproteinase and increased collagen expression in plaques62
Decreased secretion of matrix metalloproteinase 9 and THP-1 cell migration63
Yes
Generation of oxygen radicals and modulation of oxidation-sensitive signaling
Decreased LDL oxidation by macrophages64
?
Decreased SMC superoxide formation and reduced cardiac hypertrophy65
Yes
Reduced production of reactive oxygen species and improved endothelial dysfunction in normocholesterolemic hypertension66
Thrombosis / fibrinolysis
Increased fibrinolytic activity in endothelial cells67
Yes
68
Decreased platelet activation and reduced cerebral ischemia
Inhibition of tissue factor expression in macrophages69
Yes
Reduced tissue factor expression in carotid lesions70
Reduced expression of cyclooxygenase-2 in the intima and in cultured VSMCs71
Yes
NB: Opposite effects of some statins on thrombosis and fibrinolysis have been reported that cast doubts on the fact that
these effects are common to the whole class of drugs72
Clinical trials – mechanisms unknown
No indicates a significant decrease in plasma cholesterol in in vivo studies rather than evidence for cholesterol-dependent mechanisms.
?Not established or both cholesterol-dependent and -independent mechanisms.
*Opposite effects reported.
†After 2 days of treatment.
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Palinski and Napoli
quency of bleeding into plaques of the brachiocephalic
(innominate) artery was markedly reduced by statin treatment
after 6 weeks and showed a 49% reduction when all time
points were analyzed together. This was accompanied by an
even greater reduction of intraplaque calcification.
Animal models of plaque rupture have been severely
criticized in the past, and none more than murine models.12 It
is now well established that several transgenic and knockout
models develop advanced atherosclerotic lesions not only in
the aortic origin, where particular anatomic and hemodynamic conditions may influence its pathogenesis, but throughout
the entire aorta, major aortic branch sites, and coronary
arteries.13–18 The occurrence of plaque rupture in mice has
long been denied, but again “the mouse may get the last
laugh.”19 Superficial and deep plaque erosion, intraplaque
bleeding, occasional thrombi originating from the necrotic
core of advanced atheroma, and blood-filled channels consistent with revascularization of a ruptured plaque have all been
described in mice.16,20 –22 However, substantial anatomical,
physiological, and hemodynamic differences between human
and murine plaques impose a very cautious extrapolation of
the results obtained in murine models to humans. For example, the murine media consists of just a few cell layers and
their lesions have a far greater propensity to invade the media,
often resulting in the formation of aneurysms. Murine lesions
fitting the definition of early fatty streaks, ie, consisting
mainly of foam cells, frequently cause significant stenosis
that may lead to altered flow and shear stress, whereas
equivalent lesions in humans have negligible hemodynamic
consequences. Pronounced sex differences in immune-related
functions are also increasingly noted in mice, and differences
between human and murine coagulation system may exist.17
Nevertheless, human and murine vulnerable plaques have
many common features and manifestations of plaque instability may be less different than presently assumed (Figure).
Murine models would be particularly attractive because of the
relative ease with which genes implicated in atherogenesis,
arterial remodeling, and plaque rupture can be manipulated in
mice, and because microarrays are available that permit the
simultaneous assessment of the differential expression of
many murine genes in vivo.23
Bea et al focused on events in the brachiocephalic artery.
This site is particularly prone to atherogenesis and bleeding20 –22 and shows a high frequency of plaques with multiple
cap-like structures. Although alternative explanations exist,19
such lesions may indicate repeated episodes of rupture and
rapid lesion growth.22 In the mouse, these lesions are more
frequent than classical atheromas with a single fibrous cap,
but they are also seen in humans. Given the surprisingly high
frequency of erosion and rupture, it is puzzling that Bea and
colleagues did not observe intraluminal thrombi that were
noted at this site by other investigators.21,22 The low incidence
of plaque rupture and spontaneous thrombosis in other
murine arteries16 and the lack of fibrin accumulations is one
of the main arguments held against murine models. This
clearly constitutes a major practical obstacle for studies of
spontaneous plaque rupture, but one that may not persist for
long. Already, several reports have appeared in the literature
that artificially enhanced plaque vulnerability and/or in-
Pleiotropic Effects of Statins on Plaque Rupture
1747
Plaque evolution in humans and mice. Regardless of the underlying anatomical and hemodynamic differences, initial plaque
formation appears to be similar in humans and murine models
with extensive hyperlipidemia. Common features include the
progression to atheroma with a single fibrous cap and the presence of activated macrophages secreting metalloproteinases
that may waken the cap in rupture-prone areas. However, the
manifestations of plaque disruption in humans differ from those
in mice. In humans, the most frequent event associated with
clinical sequelae is a rupture of the fibrous cap leading to the
formation of thrombi that cause partial or complete occlusion of
the lumen and/or downstream embolization. Some thrombi may
also be formed as a result of plaque erosion in humans. In contrast, in apoE⫺/⫺ and LDLR⫺/⫺ mice, plaque instability mainly
takes the form of erosion and intraplaque bleeding without
thrombus formation. Plaque ruptures associated with thrombosis occur, but seem to be far less frequent than in humans.
Rupture of human plaques, even if clinically silent, results in the
transition to larger, complicated plaques. Remodeling of murine
arteries following deep erosion or rupture is poorly understood.
Repeated erosions have been postulated to cause accelerated
lesion growth20 and may be responsible for the prevalence of
lesions with multiple cap-like structures in mice, although similar
lesions have also been observed in humans. Recent data in
apoE⫺/⫺ ⫻ SR-BI⫺/⫺ mice suggest that a much greater incidence
of murine plaque instability and shifts toward rupture/thrombosis
are achievable in murine models. This should be helpful in
determining to what extent the apparent differences in plaque
instability and remodeling reflect fundamental differences in
pathogenic mechanisms.
creased the frequency of their rupture by exogenous interventions.24,25 Induced myocardial infarction, albeit without signs
of plaque rupture, have also been described.26 One may
challenge such manipulations as not being representative of
pathogenic mechanisms leading to the vulnerable plaque in
humans or its rupture.27 Most importantly, the crucial clinical
consequences– occlusive thrombi resulting in infarction and
death– have not been seen in these mice. However, better
mouse models that may overcome these important objections
are on the horizon. Crosses between apoE⫺/⫺ mice and mice
deficient for the scavenger receptor BI (SR-BI⫺/⫺) developed
by Krieger’s group are characterized by very early and
extensive atherogenesis, even when fed normal chow.28 Their
coronary atherosclerosis is comparable to that in 2-year-old
apoE mice16 and shows extensive fibrin deposits indicative of
plaque hemorrhage and coagulation. Most importantly, this is
associated with multiple spontaneous infarctions with characteristic ECG abnormalities, enlarged hearts, defects of
myocardial function (reduced ejection fraction and contractility), tissue necrosis, and death.28 This should finally put to
rest the notion that mice cannot be models of plaque rupture,
just as the development of the apoE mouse put to rest the
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1748
Arterioscler Thromb Vasc Biol.
November 2002
dogma that mice cannot develop “real” atherosclerotic lesions. It also proves in principle that conditions in mice can
be modulated to the point where their pathogenic events
mimic those in humans. This should stimulate the development of other models (see legend to the Figure). Nevertheless, models closer to the human may still be needed to
corroborate results obtained in mice.
It will probably be only a matter of time until the apoE⫺/⫺
⫻ SR-BI⫺/⫺ model will be used to investigate the mechanisms
predisposing to plaque rupture and to assess the protective
effect of statins. In the meantime, the results of Bea et al10
provide the first in vivo evidence that statins reduce plaque
vulnerability independently of cholesterol lowering. However, several caveats have to be kept in mind. The first is the
relatively high dose of statins in this and other studies.
Although a faster drug metabolism in rodents may attenuate
the physiological significance of this discrepancy, the implications in terms of the accumulation of statins or active
metabolites in cellular membranes and lipid-rich tissues in
general remain a concern. Another caveat regards the temporary rise in cholesterol. The presumption is that statins inhibit
HMG-CoA reductase and consequently the synthesis of both
cholesterol and isoprenoids in mice, as they do in humans,
and that the lack of reduction of murine plasma cholesterol
levels is solely attributable to the prevalence of lipoprotein
particles lacking the ligand for hepatic LDL receptors. If,
however, the rise in cholesterol was not coincidental and the
effect of statins on the mevanolate pathway were different
from that in humans, the relevance of the model and the
present findings would be questionable.
As indicated in the Table, in vivo evidence for genuine
pleiotropic effects of statins is sparse. The present article adds
reduced calcification, but offers no additional insights into the
mechanisms actually responsible for plaque instability. Cholesterol-independent effects of statins on lesion composition
that could contribute to weakening of the cap have previously
been established in monkeys.29 Macrophage-secreted metalloproteinases are thought to be an important cause of fibrous
cap weakening,30 although the impact of individual enzymes
has not been established.31–33 This assumption is strengthened
by the observation that pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinase expression, and cell death in human carotid
plaques.34 However, other protective effects of statins on
macrophages, T cells, and inflammatory conditions prevailing in plaques and potentially contributing to plaque rupture35
cannot be ruled out. Clearly, much more work will be
necessary to establish that specific pleiotropic effects of
statins contribute to reduced plaque vulnerability and rupture
in humans.36 – 81
References
1. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101:207–223.
2. Faggiotto A, Paoletti R. State-of-the-Art lecture: statins and blockers of
the renin-angiotensin system—vascular protection beyond their primary
mode of action. Hypertension. 1999;34:987–996.
3. Laufs U, Liao JK. Direct vascular effects of HMG-CoA reductase inhibitors. Trends Cardiovasc Med. 2000;10:143–148.
4. Napoli C, de Nigris F, Palinski W. Multiple role of reactive oxygen
species in the arterial wall. J Cell Biochem. 2001;82:674 – 682.
5. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins:
Implications for cardiovascular event reduction. JAMA. 1998;279:
1643–1650.
6. LaRosa JC. Pleiotropic effects of statins and their clinical significance.
Am J Cardiol. 2001;88:291–293.
7. Palinski W, Tsimikas S. Immunomodulatory effects of statins: Mechanisms and potential impact on arteriosclerosis. J Am Soc Nephrol.
2002;13:1673–1681.
8. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J,
Bruns C, Cottens S, Takada Y, Hommel U. Statins selectively inhibit
leukocyte function antigen-1 by binding to a novel regulatory integrin
site. Nature Med. 2001;7:687– 692.
9. Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular
agents modulating the bioactivity of nitric oxide: an overview. Circ Res.
2002;90:21–28.
10. Bea F, Blessing E, Bennet B, Levitz M, Wallace EP, Rosenfeld ME.
Simvastatin promotes atherosclerotic plaque stability in apolipoprotein E
deficient mice independently of lipid-lowering. Arterioscler Thromb Vasc
Biol. 2002;22:1832–1837.
11. Sparrow CP, Burton CA, Hernandez M, Mundt S, Hassing H, Patel S,
Rosa R, Hermanowski-Vosatka A, Wang P-R, Zhang D, Peterson L,
Detmers PA, Chao Y-S, Wright SD. Simvastatin has anti-inflammatory
and anti-atherosclerotic activities independent of plasma cholesterollowering. Arterioscler Thromb Vasc Biol. 2001;21:115–121.
12. Rekhter MD. How to evaluate plaque vulnerability in animal models of
atherosclerosis? Cardiovasc Res. 2002;54:36 – 41.
13. Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E:
evaluation of lesional development and progression. Arterioscler Thromb.
1994;14:141–147.
14. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoEdeficient mice develop lesions of all phases of atherosclerosis throughout
the aortic tree. Arterioscler Thromb. 1994;14:133–140.
15. Palinski W, Ord V, Plump AS, Breslow JL, Steinberg D, Witztum JL.
ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis: demonstration of oxidation-specific epitopes in lesions and high
titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler
Thromb. 1994;14:605– 616.
16. Calara F, Silvestre M, Casanada F, Yuan N, Napoli C, Palinski W.
Spontaneous plaque rupture and secondary thrombosis in apolipoprotein
E-deficient and LDL receptor-deficient mice. J Pathol. 2001;195:
257–263.
17. Carmeliet P, Moons L, Collen D. Mouse models of angiogenesis, arterial
stenosis, atherosclerosis and hemostasis. Cardiovasc Res. 1998;39:8 –33.
18. Palinski W, Napoli C, Reaven PD. Mouse models of atherosclerosis. In:
Simons DI, Rogers C, eds. Contemporary Cardiology: Vascular Disease
and Injury: Preclinical Research. Totowa, NJ: Humana Press; 2000:
149 –174.
19. Bennet MR. Breaking the plaque: evidence for plaque rupture in animal
models of atherosclerosis. Arterioscler Thromb Vasc Biol. 2002;1:
713–714.
20. Seo HS, Lombardi DM, Polinsky P, Powell-Braxton L, Bunting S,
Schwartz SM, Rosenfeld ME. Peripheral vascular stenosis in apolipoprotein E-deficient mice: potential roles of lipid deposition, medial
atrophy, and adventitial inflammation. Arterioscler Thromb Vasc Biol.
1997;17:3593–3601.
21. Johnson JL, Jackson CL. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis. 2001;154:399 – 406.
22. Williams H, Johnson JL, Carson KGS, Jackson CL. Characteristics of
intact and ruptured atherosclerotic plaques in brachiocephalic arteries of
apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2002;
22:788 –792.
23. Napoli C, de Nigris F, Welch J, Calara FB, Stuart RO, Glass CK, Palinski
W. Maternal hypercholesterolemia during pregnancy promotes early
atherogenesis in LDL receptor-deficient mice and alters aortic gene
expression determined by microarray. Circulation. 2002;105:1360 –1367.
24. von der Thusen JH, van Vlijmen BJ, Hoeben RC, Kockx MM, Havekes
LM, van Berkel TJ, Biessen EA. Induction of atherosclerotic plaque
rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of
p53. Circulation. 2002;105:2064 –2070.
25. Nakata Y, Maeda N. Vulnerable atherosclerotic plaque morphology in
apolipoprotein E– deficient mice unable to make ascorbic acid. Circulation. 2002;105:1485–1490.
26. Caligiuri G, Levy B, Pernow J, Thorén P, Hansson GK. Myocardial
infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci U S A. 1999;96:6920 – 6924.
Downloaded from http://atvb.ahajournals.org/ by guest on February 23, 2013
Palinski and Napoli
27. Libby P. Molecular bases of the acute coronary syndromes. Circulation.
1995;91:2844 –2850.
28. Braun A, Trigatti BL, Post MJ, Sato K, Simons M, Edelberg JM,
Rosenberg RD, Schrenzel M, Krieger M. Loss of SR-BI expression leads
to the early onset of occlusive atherosclerotic coronary artery disease,
spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E– deficient mice. Circ Res. 2002;90:
270 –276.
29. Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has
cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol. 1998;31:684 – 691.
30. Shah PK, Falk E, Badimon JJ, Fernandez-Ortiz A, Mailhac A,
Villareal-Levy G, Fallon JT, Regnstrom J, Fuster V. Human monocytederived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:
1565–1569.
31. Lemaître V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, D’Armiento
J. ApoE knockout mice expressing human matrix metalloproteinase-1 in
macrophages have less advanced atherosclerosis. J Clin Invest. 2001;107:
1227–1234.
32. Silence J, Collen D, Lijnen HR. Reduced atherosclerotic plaque but
enhanced aneurysm formation in mice with inactivation of the tissue
inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res. 2002;90:
897–903.
33. Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic
plaque but reduced aneurysm formation in mice with stromelysin-1
(MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol. 2001;21:
1440 –1445.
34. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J.
Pravastatin treatment increases collagen content and decreases lipid
content, inflammation, metalloproteinases, and cell death in human
carotid plaques: implications for plaque stabilization. Circulation. 2001;
103:926 –933.
35. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler
Thromb Vasc Biol. 2001;21:1876 –1890.
36. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala
R, Hernandez G, Diaz C, Lamas S. Effects of the 3-hydroxy-3methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on
the expression of endothelin-1 and endothelial nitric oxide synthase in
vascular endothelial cells. J Clin Invest. 1998;101:2711–2719.
37. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric
oxide synthase by HMG-CoA reductase inhibitors. Circulation. 1998;97:
1129 –1135.
38. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric
oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273:
24266 –24271.
39. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA,
Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA
reductase inhibitors mediated by endothelial nitric oxide synthase. Proc
Natl Acad Sci U S A. 1998;95:8880 – 8885.
40. Wilson SH, Simari RD, Best PJM, Peterson TE, Lerman LO, Aviram M,
Nath KA, Holmes DR Jr, Lerman A. Simvastatin preserves coronary
endothelial function in hypercholesterolemia in the absence of lipid
lowering. Arterioscler Thromb Vasc Biol. 2001;21:122–128.
41. Wilson SH, Herrmann J, Lerman LO, Holmes DR Jr, Napoli C, Ritman
EL, Lerman A. Simvastatin preserves the structure of coronary adventitial
vasa vasorum in experimental hypercholesterolemia independent of lipid
lowering. Circulation. 2002;105:415– 418.
42. Bonetti PO, Wilson SH, Rodriguez-Porcel M, Holmes DR Jr, Lerman LO,
Lerman A. Simvastatin preserves myocardial perfusion and coronary
microvascular permeability in experimental hypercholesterolemia independent of lipid lowering. J Am Coll Cardiol. 2002;40:546 –554.
43. Kimura M, Kurose I, Russell J, Granger DN. Effects of fluvastatin on
leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler Thromb Vasc Biol. 1997;17:1521–1526.
44. Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors
decrease CD11b expression and CD11b-dependent adhesion of
monocytes to endothelium and reduce increased adhesiveness of
monocytes isolated from patients with hypercholesterolemia. J Am Coll
Cardiol. 1997;30:1212–1217.
45. Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M,
Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona
M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic
protein-1 synthesis by statins. Lab Invest. 2000;80:1095–1100.
Pleiotropic Effects of Statins on Plaque Rupture
1749
46. Liu L, Moesner P, Kovach NL, Bailey R, Hamilton AD, Sebti SM, Harlan
JM. Integrin-dependent leukocyte adhesion involves geranylgeranylated
protein(s). J Biol Chem. 1999;274:33334 –33340.
47. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type
of immunosuppressor. Nature Med. 2000;6:1399 –1402.
48. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J,
Bruns C, Cottens S, Takada Y, Hommel U. Statins selectively inhibit
leukocyte function antigen-1 by binding to a novel regulatory integrin
site. Nature Med. 2001;7:687– 692.
49. Cutts JL, Scallen TJ, Watson J, Bankhurst AD. Role of mevalonic acid in
the regulation of natural killer cell cytotoxicity. J Cell Physiol. 1989;139:
550 –557.
50. Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat
primary astrocytes, microglia, and macrophages. J Clin Invest. 1997;100:
2671–2679.
51. Rudich SM, Mongini PK, Perez RV, Katznelson S. HMG-CoA reductase
inhibitors pravastatin and simvastatin inhibit human B-lymphocyte activation. Transplant Proc. 1998;30:992–995.
52. Bustos C, Hernández-Presa MA, Ortego M, Tuñón J, Ortega L, Pérez F,
Díaz C, Hernández G, Egido J. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am Coll Cardiol. 1998;32:2057–2064.
53. Inoue I, Goto S, Mizotani K, Awata T, Mastunaga T, Kawai S, Nakajima
T, Hokari S, Komoda T, Katayama S. Lipophilic HMG-CoA reductase
inhibitor has an anti-inflammatory effect: reduction of MRNA levels for
interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPAR alpha)
in primary endothelial cells. Life Sci. 2000;67:863– 876.
54. Ito T, Ikeda U, Shimpo M, Ohki R, Takahashi M, Yamamoto K, Shimada
K. HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in
human vascular smooth muscle cells. Cardiovasc Drugs Ther. 2002;16:
121–126.
55. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini
F. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1671–1678.
56. Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y,
Shiomi M, Schoen FJ, Libby P. An HMG-CoA reductase inhibitor,
cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation.;2001;
103:276 –283.
57. Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA
reductase inhibitors attenuate vascular smooth muscle proliferation by
preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol
Chem. 1999;274:21926 –21931.
58. Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ,
Diaz C, Hernandez G, Edigo J. 3-hydroxy-3-methylglutaryl coenzyme A
reductase and isoprenylation inhibitors induce apoptosis of vascular
smooth muscle cells in culture. Circ Res. 1998;83:490 –500.
59. Fukumoto Y, Libby P, Rabkin E, Hill CC, Enomoto M, Hirouchi Y,
Shiomi M, Aikawa M. Statins alter smooth muscle cell accumulation and
collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits. Circulation. 2001;103:993–999.
60. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC,
Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the
protein kinase Akt and promotes angiogenesis in normocholesterolemic
animals. Nature Med. 2000;6:1004 –1010.
61. Vincent L, Chen W, Hong L, Mirshahi F, Mishal Z, Mirshahi-Khorassani
T, Vannier JP, Soria J, Soria C. Inhibition of endothelial cell migration by
cerivastatin, an HMG-CoA reductase inhibitor: contribution to its antiangiogenic effect. FEBS Lett. 2001;495:159 –166.
62. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J.
Pravastatin treatment increases collagen content and decreases lipid
content, inflammation, metalloproteinases, and cell death in human
carotid plaques: implications for plaque stabilization. Circulation. 2001;
103:926 –933.
63. Wong B, Lumma WC, Smith AM, Sisko JT, Wright SD, Cai TQ. Statins
suppress THP-1 cell migration and secretion of matrix metalloproteinase
9 by inhibiting geranylgeranylation. J Leukoc Biol. 2001;69:959 –962.
64. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived
macrophages. Biochim Biophys Acta. 1993;1165:335–338.
65. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y,
Kitakaze M, Liao JK. Statins as antioxidant therapy for preventing
cardiac myocyte hypertrophy. J Clin Invest. 2001;108:1429 –1437.
Downloaded from http://atvb.ahajournals.org/ by guest on February 23, 2013
1750
Arterioscler Thromb Vasc Biol.
November 2002
66. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter
G, Rosen R, Bohm M, Nickenig G. HMG-CoA reductase inhibitors
improve endothelial dysfunction in normocholesterolemic hypertension
via reduced production of reactive oxygen species. Hypertension. 2001;
37:1450 –1457.
67. Essig M, Nguyen G, Prie D, Escoubet B, Sraer JD, Friedlander G.
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase
fibrinolytic activity in rat aortic endothelial cells: role of geranylgeranylation and Rho proteins. Circ Res. 1998;83:683– 690.
68. Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, Endres M.
Atorvastatin upregulates type III nitric oxide synthase in thrombocytes,
decreases platelet activation, and protects from cerebral ischemia in
normocholesterolemic mice. Stroke. 2000;31:2442–2449.
69. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins
inhibit tissue factor in cultured human macrophages: a novel mechanism
of protection against atherothrombosis. Arterioscler Thromb Vasc Biol.
17:265–272.
70. Baetta R, Camera M, Comparato C, Altana C, Ezekowitz MD, Tremoli E.
Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid
lowering. Arterioscler Thromb Vasc Biol. 2001;22:692– 698.
71. Hernandez-Presa MA, Martin-Ventura JL, Ortego M, Gomez-Hernandez
A, Tunon J, Hernandez-Vargas P, Blanco-Colio LM, Mas S, Aparicio C,
Ortega L, Vivanco F, Gerique JG, Diaz C, Hernandez G, Egido J.
Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit
model of atherosclerosis and in cultured vascular smooth muscle cells.
Atherosclerosis. 2002;160:49 –58.
72. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins:
implications for cardiovascular event reduction. JAMA. 1998;279:
1643–1650.
73. Scandinavian Simvastatin Survival Study Group. Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:
1383–1389.
74. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW,
McKillop JH, Packard CJ. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia:. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307.
75. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,
Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E.
The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels: Cholesterol and Recurrent
Events Trial investigators. N Engl J Med. 1996;335:1001–1009.
76. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
77. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D,
Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early
recurrent ischemic events in acute coronary syndromes: the MIRACL
study—a randomized controlled trial. JAMA. 2001;285:1711–1718.
78. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, Ellis
SG. Early and sustained survival benefit associated with statin therapy at
the time of percutaneous coronary intervention. Circulation. 2002;105:
691– 696.
79. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang
XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA,
Koriguchi JD, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effect
of pravastatin on outcomes after cardiac transplantation. N Engl J Med.
1995;333:621– 627.
80. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G,
Seidel D, Reichart B. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation. 1997;96:1398 –1402.
81. Ellis SG, Chew D, Chan A, Whitlow PL, Schneider JP, Topol EJ. Death
following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level,
completeness of revascularization, ventricular function, and probable
benefit of statin therapy. Circulation. 2002;106:1205–1210.
Downloaded from http://atvb.ahajournals.org/ by guest on February 23, 2013