doi: 10.1161/hh0901.090440
© 2001 American Heart Association, Inc.
Review |
Anti-Inflammatory Mechanisms in the Vascular Wall
From The Institut National de la Santé et de la Recherche Médicale, INSERM U541 and Institut Fédératif de Recherche "Circulation-Paris 7," Hôpital Lariboisière, Paris, France.
Correspondence to Alain Tedgui, PhD, INSERM U541, 41, Bd de la Chapelle, 75475 Paris, Cedex 10, France. E-mail tedgui{at}infobiogen.fr
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Abstract |
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 Top Abstract IntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
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Abstract—The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the I
B/nuclear
factor-B system. Much recent work shows that vascular inflammation
can be limited by anti-inflammatory counteregulatory mechanisms that
maintain the integrity and homeostasis of the vascular wall. The
anti-inflammatory mechanisms in the vascular wall involve
anti-inflammatory external signals and intracellular mediators. The
anti-inflammatory external signals include the anti-inflammatory
cytokines, transforming growth factor-ß, interleukin-10 and
interleukin-1 receptor antagonist, HDL, as well as some
angiogenic and growth factors. Physiological
laminar shear stress is of particular importance in protecting
endothelial cells against inflammatory activation. Its
effects are partly mediated through NO production. Finally,
endogenous cytoprotective genes or nuclear receptors, such
as the peroxisome proliferator–activated receptors, can be
expressed by vascular cells in response to proinflammatory stimuli to
limit the inflammatory process and the injury.
Key Words: endothelial cells • smooth muscle cells • inflammation • anti-inflammatory cytokines • shear stress
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Introduction |
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TopAbstractIntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
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Inflammation is a basic pathological mechanism that underlies a variety of diseases. The inflammatory reaction involves the complex interactions between inflammatory cells (neutrophils, lymphocytes, and monocytes/macrophages) and vascular cells (endothelial cells [ECs] and smooth muscle cells [SMCs]). The role of vascular cells during the inflammatory process is critical. Multiple cytokines and growth factors are present at sites of inflammation, and each of these can potentially influence the nature of the inflammatory response. ECs and SMCs must integrate the signals generated by these multiple factors to effectively regulate the immunoinflammatory response through the expression of adhesion molecules, cytokines, chemokines, matrix metalloproteinases, and growth factors. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli and resulting in the identification of major intracellular inflammatory signaling pathways, particularly the I
B/nuclear factor-B
(NF-B) system. Much recent work shows that vascular inflammation can
be limited by anti-inflammatory counteregulatory mechanisms that
maintain the integrity and homeostasis of the vascular wall. This might
be of particular importance in inflammatory diseases, such as
atherosclerosis, septic shock, or
ischemia/reperfusion. The purpose of the present review is
to describe recent advances in the understanding of the
anti-inflammatory mechanisms in vascular cells, focusing on
anti-inflammatory external signals and intracellular mediators
(Table
).
Anti-inflammatory effects of glucocorticoids will not be addressed in
this review.
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External Anti-Inflammatory Signals |
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TopAbstractIntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
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Anti-Inflammatory Cytokines
Critically situated at the boundary between blood and tissues, the endothelium is a focus for inflammatory processes. ECs receive signals from humoral factors, inflammatory mediators, and physical forces from both the circulation and the tissue. Several potential triggers capable of inducing proinflammatory and prothrombotic cellular responses have been identified; these include modified lipoproteins, proinflammatory cytokines, chemokines, vasoactive peptides, neuropeptides, hyperglycemia and advanced glycosylated end products, smoking, oxidative stress, and others.1 SMCs also are targets of these triggers. Yet the vascular inflammatory responses and their temporal patterns can be regulated by anti-inflammatory cytokines. Anti-inflammatory cytokines that exert inhibitory effects on vascular cells include transforming growth factor-ß (TGF-ß), interleukin-10 (IL-10), and IL-1 receptor antagonist (IL-1ra).
TGF-ß
TGF-ß family members are secreted in inactive
complexes with a latency-associated peptide (LAP), a protein derived
from the N-terminal region of the TGF-ß gene product.
Extracellular activation of these complexes is a critical step in the
regulation of TGF-ß function in vivo. Cytokine activation of
ECs increases TGF-ß1 synthesis and activation of latent TGF-ß by
the plasminogen/plasmin
system.2 Active TGF-ß is
produced by ECs in vitro when they are cocultured with pericytes or
SMCs.3 Production of
active TGF-ß has also been found in human arterial SMCs
in culture.4 Active TGF-ß
is detectable in the aortic wall of mice and is decreased in transgenic
mice expressing apo(a) as a consequence of apo(a) inhibition of the
plasminogen/plasmin
system.2 TGF-ß was first
reported to be a deactivating factor of macrophages capable,
for example, of suppressing inducible nitric oxide synthase (iNOS)
protein expression in
macrophages.5 TGF-ß
also has potent anti-inflammatory effects on vascular cells. TGF-ß1
downregulates cytokine-induced expression of E-selectin and
vascular cellular adhesion molecule-1 (VCAM-1) in
ECs6 7 as well as
VCAM-1 in SMCs.8 TGF-ß1
significantly decreases monocyte chemotactic protein-1 (MCP-1)
expression in human umbilical vein ECs (HUVECs) stimulated with tumor
necrosis factor-
(TNF-) or IL-1ß but not with interferon-
(IFN-).9 The expression of
TNF- receptors seems to be downmodulated by
TGF-ß1.9 Furthermore,
TGF-ß1 inhibits the elaboration of IL-8 by TNF-activated
ECs10 and inhibits the
IL-8–dependent migration of neutrophils through the activated
endothelial
monolayer.10 TGF-ß is able
to restore endothelial-dependent vasodilation impaired
by TNF-.11 In addition,
TGF-ß suppresses iNOS induction in the vascular wall, leading to the
prevention of lipopolysaccharide (LPS) shock in the
rat.12 TGF-ß expressed by
vascular cells may also operate as a paracrine anti-inflammatory
factor: glomerular mesangial cells express
TGF-ß in an active form that inhibits the production of
proinflammatory cytokines by emigrated
macrophages.13 Such
cross-communications between vascular cells and infiltrating
macrophages may play an important role in the recovery from the
inflammatory process.
The pleiotropic effects of TGF-ß are mediated from
membrane to nucleus through distinct combinations of three types of
cell-surface receptors (types I, II, and III), types I and II being
serine and threonine kinases and their downstream effectors, known as
Smad proteins.14
Smad-mediated effects result from a competitive interaction between
Smad proteins activated by TGF-ß1 and NF-B proteins
activated by proinflammatory stimuli. Smad proteins interact
with the limited amount of cAMP response element–binding protein
(CREB)-binding protein (CBP) present in ECs, therefore blocking the
association of CBP with
p65/NF-B6 that is required
for maximal transcriptional NF-B activity
(Figure 1). This type of signaling mechanism may play an
important role in the immunomodulatory actions of this
cytokine/growth factor in the cardiovascular
system.6
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Most of the anti-inflammatory effects of TGF-ß on vascular cells were documented in vitro. However, the relevance of in vitro findings to in vivo conditions is substantiated by the observation that TGF-ß1–deficient mice die in utero or in the perinatal period because of widespread uncontrolled inflammation.15 The TGF-ß1 knockout mice have multifocal inflammatory disease in many tissues, but the heart and lungs are most severely affected. Increased adhesion of leukocytes to the endothelium of pulmonary veins and increased expression of major histocompatibility complex (MHC) class I and II proteins are seen in pulmonary vascular endothelium as early as day 8.16
Mice heterozygous for the deletion of the TGF-ß1 gene (TGF-ß1+/- mice) show higher levels of endothelial intercellular adhesion molecule-1 (ICAM-1) and VCAM-1 and enhanced macrophage infiltration than the wild-type mice after 12 weeks of cholesterol-enriched diet.17 These findings suggest that the presence of endogenous TGF-ß1 in the vessel wall is protective against vascular inflammation.
IL-10
IL-10 is a pleiotropic cytokine produced by
Th2-type T cells, B cells, monocytes, and macrophages that
inhibits a broad array of immune parameters, including Th1
lymphocyte cytokine production, antigen
presentation, and antigen-specific T-cell proliferation.
IL-10 also has potent anti-inflammatory properties on
macrophages. In vitro experiments showed that the expression of
IL-10 in LPS-stimulated monocytes is delayed relative to that of other
proinflammatory cytokines (TNF- and IL-1) and coincides with
their downregulation. Moreover, in vivo studies showed that plasma
TNF- levels are higher and remained elevated for a much longer
period of time in IL-10–deficient
(IL-10-/-) mice injected with LPS than
in IL-10+/+
mice.18 It therefore seems
that IL-10 acts in a feedback loop to inhibit continued proinflammatory
cytokine production.
In vitro cell culture systems have yielded conflicting
insights into the modulatory actions of IL-10 on ECs and SMCs. Most of
the studies failed to demonstrate any direct anti-inflammatory effect
on the expression by ECs of adhesion
molecules,19
chemokines,20
colony-stimulating
factors,21 IL-6
production,22 or
IFN- induction of class II MHC surface
antigen.23 Similarly, IL-10
had no effect on IL-8 and MCP-1 release by human aortic SMCs in
response to IL-1 or
TNF-.24 Lack of direct
effects of IL-10 on vascular cells in vitro might be attributable to
the lack of IL-10 receptor or to an impairment of the complex
intracellular IL-10 signaling pathway. Moreover, the effects of IL-10
on vascular cells may vary according to the origin of the cells and the
signaling pathways induced by the proinflammatory stimuli. Accordingly,
in other studies it was found that IL-10 downregulates the expression
of ICAM-1 and VCAM-1 on IL-1–activated
HUVECs,25 decreases both
IL-8 and IL-6 production by irradiated
HUVECs,26 inhibits
TNF-induced or fibroblast growth factor-2 (FGF-2)–induced human aortic
SMC proliferation,27 and
partially antagonizes IFN-–induced expression of the secretory
nonpancreatic phospholipase A2 in human
SMCs.28 Moreover,
pretreatment of human aortic ECs with recombinant IL-10 as well as
transfection with an adenovirus expressing viral IL-10 causes a
significant decrease in minimally modified LDL-induced monocyte
binding.29 Interestingly,
these latter observations are supported by in vivo findings in mice
showing that electrotransfer of IL-10 cDNA results in significant
decrease in endothelial NF-B activation and in
expression of VCAM-1 and ICAM-1 after 10 days on a high-fat
diet.30
IL-10 exerts its biological effects on cells by interacting
with a specific cell-surface receptor. Functionally active IL-10
receptor is composed of two distinct subunits. Both subunits belong to
the class II cytokine receptor family. The IL-10 receptor
chain (or IL-10R1) plays the dominant role in mediating high-affinity
ligand binding and signal
transduction.31 The IL-10
receptor ß subunit (IL-10R2, also known as the orphan receptor
CRF2-4) serves as an accessory chain essential for the active IL-10
receptor complex and to initiate IL-10–induced signal transduction
events.32 Studies using
macrophages from mice with disrupted genes for Jak1, Stat1, or
Stat3 have revealed an obligate role for Jak1and Stat3 in mediating the
anti-inflammatory actions of
IL-10.33 In addition to the
Janus kinase/signal transducers and activators of
transcription (JAK-STAT) pathway, the presence of a carboxyl-terminal
sequence containing at least one functionally critical serine on the
intracellular domain of the IL-10 receptor chain is required for
expression of the anti-inflammatory actions of
IL-10.33
IL-10 functions to block NF-B activity through both the
suppression of IB kinase activity, preventing IB degradation,
and the suppression of NF-B DNA-binding
activity34
(Figure 1
). IL-10 also affects signaling through
extracellular signal–regulated kinase (ERK) 1 and ERK2 and other
mitogen-activated protein kinase (MAPK) pathways that are
potentially important for chemokine and cytokine
induction35 and destabilizes
the mRNA of proinflammatory genes with clustered AU-rich
elements motifs.36 So far,
nothing is known concerning the expression of IL-10 receptor and
ß chains and the complex IL-10 signaling pathway in vascular
cells.
In vivo, IL-10 most likely exerts its anti-inflammatory
effects on the vascular system through inhibition of leukocyte-EC
interactions37 38 39 40
and inhibition of proinflammatory cytokine and chemokine
production by macrophages or
lymphocytes.41 42 43
In an acute lung injury model, IL-10 significantly decreased lung
injury and ICAM-1 levels through decrease in TNF-
levels.37 LPS-induced
expression of ICAM-1 and VCAM-1 in the vasculature of the small
intestine and leukocyte adhesion in mesenteric venules are markedly
increased in IL-10–deficient mice compared with wild-type animals,
underlining the inhibitory role of endogenous
IL-10 in the control of intestinal vascular
inflammation.38 40
Transfected viral IL-10 decreases leukocyte vein extravasation through
a decrease in endothelial expression of P- and
E-selectin and ICAM-1.40
IL-10 similarly blunts inflammation secondary to myocardial
ischemia/reperfusion through an ICAM-1–dependent
mechanism44 and reduces
liver injury and mortality in a mouse septic shock model through
decreased neutrophil margination and ICAM-1 and VCAM-1
expression.45
Endogenous IL-10 might also be produced during myocardial
ischemia-reperfusion by lymphocytes infiltrating the reperfused
myocardium and could limit myocardial macrophage
activation.46
The protective effect of IL-10 against the development of diet-induced atherosclerosis could also be attributed to inflammatory cell deactivation. Expression of IL-10 in the atherosclerotic lesion42 47 is associated with low iNOS expression by macrophages and low levels of cell death.42 In addition, atherosclerotic lesions of IL-10-/- mice fed an atherogenic diet are characterized by increased infiltration of inflammatory cells, particularly activated T cells, and by increased production of proinflammatory cytokines, underscoring the anti-inflammatory actions of IL-10 produced within the atherosclerotic plaque.43 In a model of balloon angioplasty or stent implantation in hypercholesterolemic rabbits, treatment with recombinant human IL-10 markedly reduced macrophage infiltration and intimal hyperplasia.48 Additional mechanisms of vascular protection by endogenous IL-10 include decreased superoxide anion production in blood vessels in response to LPS, which prevents the impairment of endothelium-dependent relaxation.49
It is noteworthy that IL-10 most likely exerts its anti-inflammatory effect when produced locally in the vascular wall. Chronic production of high levels of IL-10 in the systemic circulation may instead lead to immunostimulatory effects.
IL-1 Receptor Antagonist
IL-1 is one of the most potent proinflammatory
cytokines acting on both ECs and
SMCs.1 Processed mature IL-1
signals via the type I IL-1 receptor but also binds to a nonsignaling
receptor (IL-1 receptor type II). The IL-1 receptor
antagonist (IL-1ra) is an endogenous secreted
protein that binds to IL-1 type I and II receptors without signaling.
An intracellular form of IL-1ra is expressed by human ECs and
SMCs,50 51 but
its role remains unclear. However, in vivo studies reveal that IL-1ra
does have vascular protective effects. Treatment with recombinant
IL-1ra inhibits fatty streak formation in
apoE-/-
mice.52 More importantly,
IL-1ra knockout mice develop lethal chronic inflammation of the
arterial wall, associated with massive transmural
infiltration of neutrophils, macrophages, and
CD4+ lymphocytes in branch points and
flexures of the aorta and in its primary and secondary
branches.53 Additional
support for a vascular role of IL-1ra is provided by the recent
observation of an association between IL-1ra gene polymorphism and
coronary artery
disease.54
Th2 Anti-Inflammatory Cytokines IL-4
and IL-13
Th2 cytokines IL-4 and IL-13 suppress the
production of inflammatory cytokines by
macrophages and monocytes and are considered anti-inflammatory
cytokines. However, IL-4 and IL-13 selectively induce VCAM-1
and P-selectin expression on ECs with no effect on ICAM-1 or
E-selectin.55 56 57
IL-13 markedly enhances IL-8 and MCP-1 release by
cytokine-stimulated human
SMCs24 but inhibits NOS II
expression in LPS-activated rat
SMCs.58 In vivo studies
indicate that IL-4 and IL-13 are capable of promoting
angiogenesis57 and that IL-4
plays a role in the progression of early inflammatory atherosclerotic
lesions driven by immunization against heat shock protein
65.59 This may be
consistent with the recently reported switch from Th1 to Th2
responses during atherosclerosis progression in
severely hypercholesterolemic
apoE-/-
mice.60 However, it remains
unknown to what extent this switch might affect lesion progression. In
general, it seems that the macrophages deactivating
cytokines IL-4 and IL-13 display proinflammatory activities in
the vascular system.
High-Density Lipoprotein
There is abundant evidence from epidemiological studies
that HDL plasma concentration is inversely correlated with the
occurrence of coronary artery disease. Besides the effects of
HDL on the promotion of cholesterol efflux and protection
against lipid peroxidation, it exerts potent anti-inflammatory
activities on ECs. HDL inhibits cytokine-induced expression
of E-selectin, ICAM-1, and VCAM-1 on ECs at the transcriptional
level.61 62 63 64
The effects of HDL seem to be related to its phospholipid
content.63 The
anti-inflammatory effects of HDL on ECs could involve the sphingosine
kinase (SphK) pathway through the generation of sphingosine 1 phosphate
(S1P).65 HDLs inhibit the
TNF-induced SphK activity and S1P generation and are expected to
subsequently reduce the activation of ERK and NF-B signal cascades
(Figure 1). However, other studies reported that the
anti-inflammatory effects of HDL are not mediated by a direct
inhibition of the NF-B pathway, because HDLs do not inhibit IB
degradation or the nuclear translocation of
NF-B.62 Furthermore, HDLs
inhibit E-selectin expression in response to proinflammatory
cytokines but have no effect on the expression of
NF-B–dependent genes, such as granulocyte-macrophage
colony-stimulating factor (GM-CSF) and COX-2. Interestingly, HDLs also
stimulate COX-2 expression in
SMCs,66 which suggests that
the anti-inflammatory effect of HDL might be restricted to a specific
set of genes.
Whatever the molecular mechanisms of the anti-inflammatory effects of HDL, the pathophysiological relevance of the ability of HDL to exert these activities is substantiated by several studies showing that HDLs inhibit endothelial cell adhesion molecule expression in vivo. Elevation of the circulating levels of HDL inhibits E-selectin expression by microvascular ECs in a porcine model of acute inflammation,64 and reconstituted HDL containing human apoA-I reduces VCAM-1 expression in common carotid artery after inflammation associated with periadventitial cuff-induced injury in apoE-/- mice.67
Angiogenic and Growth Factors
VEGF is a potent factor in increasing permeability of
endothelial cells that leads to the passage of plasma
components and leukocytes from the blood vessel into the tissues and
may therefore contribute to the inflammatory response. Yet VEGF might
exert anti-inflammatory protective functions by stimulating
endothelial NO
production,68 which
may inhibit leukocyte recruitment (see below). The receptor mediating
VEGF-induced NO production in ECs is likely to be VEGF
receptor-2.69 This effect is
mediated by a signaling cascade initiated by flk-1/KDR
activation of c-Src, leading to phospholipase C1 activation,
inositol 1,4,5-trisphosphate formation, release of intracellular
Ca2+, and NOS
activation.69
Angiopoietin-1 (Ang-1), the ligand of the
endothelium-specific tyrosine kinase receptor Tie-2,
has been shown to be an anti-inflammatory agent in
vitro.70 Ang-1 pretreatment
of ECs abolished TNF-–induced transmigration. This effect likely
results from enhanced platelet EC adhesion molecule-1 (PECAM-1)
localization to the EC
junctions.70 Interestingly,
hypoxia and inflammatory cytokines upregulate Tie2
receptor in HUVECs and human microvascular
EC-1.71 In this context,
enhancement of PECAM-1 or PECAM-1 engagement mediated by Ang-1 might
promote a noninflammatory phenotype of ECs.
Growth factors not only modulate vascular cell survival and growth but also may act as modulators of inflammatory responses. FGF-2 can inhibit endothelial expression of tissue factor and other inflammatory genes, including tissue plasminogen activator, plasminogen activator inhibitor-2, and IL-8, in response to phorbol myristate acetate.72 Exposure of ECs to FGF-2 or FGF-1/heparin also inhibits cytokine-mediated expression of ICAM-1, VCAM-1, E-selectin, and COX.73 74 However, this anti-inflammatory effect of FGF-1 and FGF-2 seems to be EC-specific, because FGF-2 induces tissue factor expression in fibroblasts, monocytes, and SMCs.75 In SMCs, growth factors may have ambiguous effects. Platelet-derived growth factor induces MCP-176 and ICAM-1,77 whereas it inhibits cytokine-stimulated expression of NOS II and NO release.78
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Intracellular Anti-Inflammatory Mediators |
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Regulators of NF-
B Signaling PathwayThe expression of inducible genes leading to the synthesis of cytokines, chemokines, adhesion molecules, and autacoids relies on transcription factors. Among the primary transcription factors, NF-
B plays a central role in the regulation
of inflammatory mediators.79
Events leading to the activation of NF-B rely on the
phosphorylation of IB followed by its
ubiquitination and proteolytic degradation into the proteasome.
Phosphorylation of IB depends on a IB kinase
(IKK) complex containing two kinases, IKK and IKKß, and the
regulatory protein NEMO (NF-B essential modifier, also named
IKK).80 Moreover, NF-B
itself induces the synthesis of IkB to regenerate an inactive form
of NF-B and ensures the transiency of NF-B activation. The
intracellular redox status of the cell is extremely important in the
regulation of NF-B/IB by preventing the activation of IB
kinase.81 Antioxidants,
aspirin,
N-acetyl-L-cysteine
(NAC), and flavonoids may inhibit the activation of NF-B. We have
seen that TGF-ß and IL-10 negatively regulate the NF-B pathway.
Glucocorticoids enhance the formation of IB, and several
constitutive or inducible cytoprotective genes have been shown to
inhibit NF-B activity in ECs (see below). NO also inhibits NF-B
activity in ECs through the induction and stabilization of IB
(see below). The activation of NF-B can also be attenuated by
inhibiting the proteolytic degradation of IB in the proteasome. A
naturally occurring antibacterial peptide, PR39, which reversibly binds
the 26S proteasome and blocks the degradation of IB by the
ubiquitin-preoteasome pathway, suppresses VCAM-1 and ICAM-1 gene
expression in TNF-–activated human ECs and reduces the size
of myocardial infarction in an in vivo mouse model of coronary
ligature.82 Another
possibility to interrupt the NF-B pathway is to block the
interaction between NEMO and
IKKß.83 A cell-permeable
NEMO-binding domain (NBD) peptide able to disrupt the IKKß-NEMO
interaction efficiently reduces E-selectin expression in
TNF-–treated HUVECs.83
These anti-inflammatory agents (PR39 and NBD peptide) that directly
interact intracellularly with the NF-B pathway
(Figure 1) might prove to be useful tools to block
proinflammatory activation in the vascular wall.
Protective Genes
Endogenous protective genes can be
expressed by vascular cells to limit the inflammatory process and
injury. Indirect arguments suggest that both ECs and VSMCs may develop
an autoprotective phenotype during inflammation.
Cytoprotective Genes
In addition to protecting ECs from apoptosis,
several antiapoptotic genes have been shown to possess potent
anti-inflammatory properties
(Figure 2). As a consequence, they have been named
cytoprotective genes. These include members of the Bcl-2 family (Bcl-2,
Bcl-xL, and A1), A20, and heme
oxygenase-1 (HO-1). A1 and A20 are induced in response to
inflammatory stimuli to protect ECs from unfettered activation and from
undergoing apoptosis even when NF-B is
blocked.84 Overexpression of
Bcl-2, Bcl-xL, A1, or A20 inhibits VCAM-1,
E-selectin, and IL-8 expression in ECs by inhibiting NF-B
activation.85 86
In vivo experiments underscore the importance of these protective genes
in organ xenografts. ECs in hamster hearts that accommodate themselves
in rats express certain genes, such as A20 and bcl-2, whereas hearts
that are rejected do not express these
genes.87 In addition,
vessels of rejected hearts show florid transplant
arteriosclerosis, whereas those of accommodated
hearts do not. Moreover, studies in mice deficient for A20 confirm the
critical role of this protective gene for limiting TNF-–dependent
NF-B activation and
inflammation.88 A20 knockout
mice develop severe inflammation and cachexia, are hypersensitive to
both LPS and TNF, and die prematurely. Taken together, these data
suggest that A1 and A20 offer the mean of achieving an
anti-inflammatory effect in the vascular wall.
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HOs also belong to the family of cytoprotective genes. HOs catalyze the rate-limiting step in the degradation of heme to yield equimolar amounts of biliverdin, carbon monoxide, and iron. Besides their antiapoptotic effect, there is a growing body of evidence that ascribes an anti-inflammatory role for the products of the inducible form of HO (HO-1).89 HO-1 can be upregulated in human ECs by TNF and IL-1.90 In particular, exogenous administration of HO-1 by gene transfer protects the rat lung against hyperoxia-induced neutrophil infiltration and tissue injury.91 Moreover, HO-1 deficiency in humans is associated with the presence of severe and persistent endothelial damage.92
Fas and Fas Ligand
Fas ligand (FasL) is a death factor that induces
apoptosis in Fas-bearing cells. FasL is constitutively
expressed on ECs but not in
SMCs.93 Local administration
of TNF- to arteries downregulates endothelial FasL
expression and induces mononuclear cell infiltration, whereas FasL
overexpression markedly attenuates TNF-–induced cell infiltration.
Moreover, adherent mononuclear cells undergo apoptosis rather
than diapedesis under these conditions as a result of Fas-FasL
ligation. These data suggest that endothelial FasL
plays an active role in inhibiting leukocyte extravasation and vascular
inflammation. Recent experiments in FasL-deficient mice additionally
support this contention.94
In a model of flow restriction in the common carotid artery, vascular T
lymphocyte and macrophage infiltration after flow restriction
is notably enhanced in FasL knockout mice compared with wild-type mice.
Moreover, the flow-restricted common carotid arteries develop greater
neointima formation in FasL knockout mice than in wild-type
mice.
Serpine Proteinase Inhibitor
9
SMCs and ECs express the 33-kDa precursors of both IL-1
and IL-1ß as cell-associated proteins, but SMCs neither contain
mature IL-1ß nor are able to process recombinant IL-1ß precursor
into its mature 17-kDa form. Despite this failure, SMCs express
IL-1–converting enzyme but possess in their cell membrane compartment
an inhibitory factor of IL-1ß processing, recently
identified as the serpine proteinase inhibitor 9
(PI-9).95 PI-9 is
homogenously expressed in the normal arterial wall, and its
expression inversely correlates with immunoreactive IL-1ß in the
atherosclerotic plaque, suggesting a potential role for PI-9 in this
inflammatory disease.
Nitric Oxide
Besides its action on vasomotor tone regulation,
endothelium-derived NO has been recognized to be an
anti-inflammatory molecule. Endogenous NO synthesis
inhibits leukocyte rolling and adhesion as well as
cytokine-induced expression of ICAM-1 and
VCAM-1.96 97 NO
inhibits M-CSF synthesis in
ECs.98 Furthermore,
inhibition of basal NO production by
NG-nitro-L-arginine
in human ECs upregulates and exogenous addition of NO decreases MCP-1
expression.99 NO donors
inhibit the expression of MCP-1 in SMCs exposed to LPS or oxidized
LDL100 and diminish VCAM-1
expression induced by
IFN-.101 The
anti-inflammatory effects of NO are attributable, at least in part, to
inhibition of NF-B activation through increased expression and
nuclear translocation of
IB97 102
(Figure 3). The crucial role of NO as an
endogenous anti-inflammatory mediator was later
substantiated by in vivo experiments of chronic inhibition of NO
synthesis. Administration of the NO synthesis inhibitor
N
-nitro-L-arginine
methyl ester (L-NAME) induces vascular monocyte infiltration, MCP-1,
IL-6, M-CSF, ICAM-1, and VCAM-1 expression as well as NF-B
activation.103 104 105 106
In vivo transfection of cis
element decoy oligodeoxynucleotides against NF-B
prevents the L-NAME–induced early inflammation, suggesting that the
NF-B pathway is essential in this
process.104 Along with
inflammatory changes, vascular superoxide anion production is
also increased after chronic NO blockade, and the antioxidant NAC
prevents all of these
changes.106 107
Therefore, inhibition of NO synthesis increases vascular oxidative
stress leading to inflammatory responses. Interestingly, in
L-NAME–induced vascular inflammation, treatment with an
angiotensin II type 1 receptor antagonist also
prevents NF-B activity and the consequent inflammatory
changes.103 107
Taken together, these data suggest that endogenous
endothelial NO decreases proinflammatory oxidative
stress-sensitive signals by suppressing localized activity of
angiotensin II in blood vessels.
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Peroxisome Proliferator–Activated
Receptors
Peroxisome proliferator–activated
receptors (PPARs) are transcription factors belonging to the nuclear
receptor superfamily, of which three different PPAR subtypes have been
identified, PPAR, PPARß/
, and PPAR. PPARs regulate gene
expression by binding with the retinoid receptor RXR as a heterodimeric
partner to specific DNA sequence elements termed PPAR-responsive
elements. Fatty acid derivatives and eicosanoids have been identified
as natural ligands for
PPARs.108 Furthermore,
fibrates are synthetic ligands for PPAR that mediate the
lipid-lowering activity of these drugs, and the antidiabetic
thiazoldinediones are synthetic ligands for PPAR. PPAR and
PPAR have been found to be expressed in both
ECs109 110 and
SMCs111 112 113
in vitro and in vivo in the human atherosclerotic
plaque.114 115 116
Anti-inflammatory actions of PPARs were first reported in monocytes and
macrophages for
PPAR.117 118
Thereafter, PPAR activation, but not PPAR, was shown to repress
cytokine-induced activation of COX-2 and IL-6 in human
SMCs111 and VCAM-1 in human
ECs, resulting in reduced functional adhesion of
monocytes.119 These in
vitro findings are in good agreement with an earlier study showing that
PPAR knockout mice have increased acute inflammatory
responses.120 Moreover,
recent findings clearly indicate that PPAR has anti-inflammatory
properties in the vascular wall; aortic explants isolated from PPAR
knockout mice display an exacerbated response to inflammatory stimuli,
resulting in increased IL-6 production compared with wild-type
mice.113 Furthermore,
fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas
of wild-type mice but not of PPAR knockout mice.
In addition to regulating gene transcription via PPAR
responsive elements, PPARs have recently been shown to modulate gene
transcription by interfering with other transcription factor pathways
in a DNA binding–independent
manner.111 113 117 119
PPARs have been shown to downregulate inflammatory response genes by
negatively interfering with the STAT, AP-1, and NF-B transcriptional
pathways.109 111 113 117 119
For example, direct protein-protein interactions between PPAR and
AP-1 and NF-B proteins have been invoked as mechanisms of
transrepression.113 In
addition, by regulating antioxidant enzyme activities, such as
catalase,121 PPAR
activators reduce the oxidative stress and, as a result,
may inhibit NF-B activation. Finally, PPAR activators
may antagonize NF-B activation through the expression of the
inhibitory protein IB, as shown in
IL-1ß–stimulated human aortic SMCs in the presence of
fibrates122
(Figure 1).
Several years ago, the n-3 fatty acid docosahexaenoic
acid docosahexaenoic acid was reported to limit
cytokine-induced expression of VCAM-1 and other
proinflammatory mediators in human
ECs.123 We now know that
this is likely attributable to the anti-inflammatory activities of
PPAR, which is a target for various long-chain fatty acids,
including n-3 fatty
acids.124
The anti-inflammatory activities of PPAR take on
particular significance in view of the findings that fibrate treatment
decreases plasma concentrations of inflammatory cytokines in
patients with angiographically established
atherosclerosis.111
Furthermore, the recent Veteran’s Administration HDL Intervention
Trial showed a beneficial effect of the fibrate gemfibrozil on
atherosclerotic events that could not be accounted for by reductions in
LDL
concentrations.125
|
Anti-Inflammatory Effects of Shear Stress |
|---|
|
TopAbstractIntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
|---|
Apart from humoral stimuli, ECs are constantly exposed to a spectrum of hemodynamic forces generated by pulsatile blood flow, hydrostatic pressure, cyclic strains, and wall shear stresses.126 Biomechanical forces induce endothelial structural changes and modulate gene expression.127 Most in vitro experiments using ECs suggest that physiological levels of shear stress are essentially anti-inflammatory and antiadhesive. Prolonged exposure of ECs to laminar flow, as occurs in vivo, results in downregulation of ICAM-1 and VCAM-1,128 whereas prolonged low or oscillatory shear-stress conditions enhance monocyte adhesion and VCAM-1, ICAM-1, and E-selectin expression.129 130 Anti-inflammatory effects of laminar shear stress may also prevail in conditions of activated ECs. Chronic laminar shear stress suppresses VCAM-1 expression by IL-1ß–stimulated ECs, whereas oscillatory shear stress has no effect.130 Similarly, monocyte adhesion to ECs in the presence of oxidized lipids is markedly reduced by physiological pulsatile unidirectional flow, whereas oscillatory flow promotes monocyte adhesion.131 These in vitro studies are in agreement with in vivo experiments showing that low or oscillatory shear stress provides a proinflammatory stimulus to ECs.30 132 133 Constitutive NF-
B activation and VCAM-1 expression are seen in ECs
located in aortic regions of high probability for atherosclerotic
lesion development, which are known to be regions of altered
hemodynamics
forces.30 133
Moreover, chronically decreased blood flow in rabbits stimulates VCAM-1
expression and enhances monocyte
adhesion.132
Molecular mechanisms of anti-inflammatory actions of shear
stress involve protection against oxidative stress and inhibition of
NF-B and jun-N-terminal kinase (JNK)–AP-1 pathways
(Figure 3). Laminar shear stress induces Cu/Zn superoxide
dismutase,134 135
suggesting that absence or decrease of shear stress results in
increased production of superoxide radicals. In contrast, low
or oscillatory flow patterns induce a sustained activation of
pro-oxidant processes, resulting in redox-sensitive gene
expression.129 136
The antioxidant pyrrolidine dithiocarbamate, but not NAC, strongly
inhibits low shear–induced NF-B activation, expression of VCAM-1,
and monocyte adhesion.129
Because NAC seems to have no effect on superoxide
radical,137 it is tempting
to hypothesize that low shear stress allows
O2--dependent
activation of NF-B and subsequently VCAM-1. However, both
pyrrolidine dithiocarbamate and NAC inhibit NF-B activation and
VCAM-1 expression induced by oscillatory shear stress or
cytokines, suggesting that other pro-oxidant pathways may be
involved
(H2O2/OH ·-sensitive
mechanisms).129 130
Taken together, these data also indicate that ECs discriminate between
various types of flow and between flow and cytokine
stimulation.
Other mechanisms may account for the anti-inflammatory
actions of shear stress. The MAPK JNK is activated by exposure
of cells to cytokines or environmental stress and contributes
to inflammatory
responses.138 Laminar shear
stress specifically inhibits cytokine-induced JNK activity
but has no effect on the other
MAPKs.139 Shear stress also
abrogates the complement-induced IL-8 and MCP-1 expression in ECs
through upregulation of the complement-inhibitory protein
clustering.140 In addition,
shear stress upregulates the expression of the inhibitory
adapter protein tumor necrosis receptor-associated factor (TRAF)-3, and
transfection of a dominant-negative TRAF3 mutant reverses the
inhibitory effect of shear stress on CD40-induced MCP-1
expression.141 Finally,
shear stress is known to be the physiological
activator/inducer of NOS III, and NO has anti-inflammatory
actions by scavenging
O2- and through
inhibition of NF-B pathway (see
above).
|
Conclusions |
|---|
|
TopAbstractIntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
|---|
The involvement of vascular inflammation in several pathological conditions, including atherosclerosis, ischemia/reperfusion, hypertension, restenosis, angiogenesis, septic shock, and cerebral malaria, has only recently been fully revealed. In the context of atherosclerosis, the inflammatory response seems to determine the development of the disease from even the site and extent of endothelial activation to lesion growth and lesion complications. This is consistent with clinical studies in humans showing a major prognostic and independent value for markers of inflammation in predicting the occurrence of ischemic vascular events.142 Great progress has been made during the last decade in the understanding of the molecular mechanisms that mediate the inflammatory responses in vascular cells. The identification of protective anti-inflammatory mechanisms is much more recent. Interestingly, several effects of some well-known antiatherogenic and vasculoprotective agents, including HDL, statins, fibrates, NO, shear stress, antioxidants, and n3-fatty acids, might in fact be attributable, at least in part, to their anti-inflammatory properties. More importantly, recent data suggest that vascular cells may develop genetically determined intrinsic anti-inflammatory mechanisms.143 Delineating these anti-inflammatory pathways will be one of the challenging future objectives in vascular biology, which could yield promising novel therapeutic possibilities. Yet such anti-inflammatory strategies should be specifically targeted at the diseased tissue, particularly when long-term therapy is necessary, to limit potential side effects.
|
Acknowledgments |
|---|
This work was supported by INSERM, Fondation de France, and Fondation pour la Recherche Médicale.
|
Footnotes |
|---|
Original received February 6, 2001; revision received March 14, 2001; accepted March 20, 2001.
This Review is part of a thematic series on Inflammatory Mechanisms in Atherosclerosis, which includes the following articles:
Anti-Inflammatory Mechanisms in the Vascular Wall
Clinical Imaging of the High-Risk or Vulnerable Atherosclerotic Plaque
Innate and Adaptive Immune Mechanisms in Atherosclerosis
CD40 Signaling and Plaque Instability
Novel Clinical Markers of Vascular Wall Inflammation
Andreas Zeiher, Guest Editor
|
References |
|---|
|
TopAbstractIntroductionExternal Anti-Inflammatory...Intracellular Anti-Inflammatory...Anti-Inflammatory Effects of...ConclusionsReferences |
|---|
1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126.
2. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-ß is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994;370:460–462.[Medline] [Order article via Infotrieve]
3. Axel DI, Riessen R, Athanasiadis A, Runge H, Koveker G, Karsch KR. Growth factor expression of human arterial smooth muscle cells and endothelial cells in a transfilter coculture system. J Mol Cell Cardiol. 1997;29:2967–2978.[Medline] [Order article via Infotrieve]
4.
Kirschenlohr HL,
Metcalfe JC, Weissberg PL, Grainger DJ. Adult human aortic smooth
muscle cells in culture produce active TGF-ß.
Am J Physiol. 1993;265:C571–C576.
5.
Vodovotz Y, Bogdan
C, Paik J, Xie QW, Nathan C. Mechanisms of suppression of
macrophage nitric oxide release by transforming growth
factor-ß. J Exp Med. 1993;178:605–613.
6.
DiChiara MR, Kiely
JM, Gimbrone MA Jr, Lee ME, Perrella MA, Topper JN. Inhibition of
E-selectin gene expression by transforming growth factor ß in
endothelial cells involves coactivator
integration of Smad and nuclear factor B-mediated signals.
J Exp Med. 2000;192:695–704.
7.
Park SK, Yang WS,
Lee SK, Ahn H, Park JS, Hwang O, Lee JD. TGF-ß1 down-regulates
inflammatory cytokine-induced VCAM-1 expression in cultured
human glomerular endothelial cells.
Nephrol Dial Transplant. 2000;15:596–604.
8.
Gamble JR, Bradley
S, Noack L, Vadas MA. TGF-ß and endothelial cells
inhibit VCAM-1 expression on human vascular smooth muscle cells.
Arterioscler Thromb Vasc Biol. 1995;15:949–955.
9.
Honda HM, Leitinger
N, Frankel M, Goldhaber JI, Natarajan R, Nadler JL, Weiss JN, Berliner
JA. Induction of monocyte binding to endothelial cells
by MM-LDL: role of lipoxygenase metabolites.
Arterioscler Thromb Vasc Biol. 1999;19:680–686.
10. Smith WB, Noack L, Khew-Goodall Y, Isenmann S, Vadas MA, Gamble JR. Transforming growth factor-ß1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium. J Immunol. 1996;157:360–368.[Abstract]
11.
Lefer AM, Tsao P,
Aoki N, Palladino MA Jr. Mediation of cardioprotection by transforming
growth factor-ß. Science. 1990;249:61–64.
12.
Perrella MA,
Patterson C, Tan L, Yet SF, Hsieh CM, Yoshizumi M, Lee ME. Suppression
of interleukin-1ß-induced nitric-oxide synthase promoter/enhancer
activity by transforming growth factor-ß1 in vascular smooth muscle
cells: evidence for mechanisms other than NF-B.
J Biol Chem. 1996;271:13776–13780.
13. Kitamura M, Suto T, Yokoo T, Shimizu F, Fine LG. Transforming growth factor-ß1 is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells. J Immunol. 1996;156:2964–2971.[Abstract]
14.
Topper JN.
Transforming growth factor-ß (TGF-ß) and vascular disease: CARP as
a putative TGF-ß target gene in the vessel wall.
Circ Res. 2001;88:5–6.
15. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschman T. Targeted disruption of the mouse transforming growth factor-ß1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–699.[Medline] [Order article via Infotrieve]
16. Kulkarni AB, Ward JM, Yaswen L, Mackall CL, Bauer SR, Huh CG, Gress RE, Karlsson S. Transforming growth factor-ß1 null mice: an animal model for inflammatory disorders. Am J Pathol. 1995;146:264–275.[Abstract]
17. Grainger DJ, Mosedale DE, Metcalfe JC, Bottinger EP. Dietary fat and reduced levels of TGFß1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000;113:2355–2361.[Abstract]
18. Berg DJ, Kuhn R, Rajewsky K, Muller W, Menon S, Davidson N, Grunig G, Rennick D. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest. 1995;96:2339–2347.
19. Noble KE, Harkness D, Yong KL. Interleukin 10 regulates cellular responses in monocyte/endothelial cell co-cultures. Br J Haematol. 2000;108:497–504.[Medline] [Order article via Infotrieve]
20. Parks E, Lukacs NW, Strieter RM, Kunkel SL. Chemokine expression in endothelial cells and monocytes is differentially regulated. Pathobiology. 1998;66:64–70.[Medline] [Order article via Infotrieve]
21. Lenhoff S, Olofsson T. Cytokine regulation of GM-CSF and G-CSF secretion by human umbilical cord vein endothelial cells (HUVEC). Cytokine. 1996;8:702–709.[Medline] [Order article via Infotrieve]
22. Sironi M, Munoz C, Pollicino T, Siboni A, Sciacca F, Bernasconi S, Vecchi A, Colotta F, Mantovani A. Divergent effects of IL-10 on cytokine production by mononuclear phagocytes and endothelial cells. Eur J Immunol. 1993;23:2692–2695.[Medline] [Order article via Infotrieve]
23. Leclaire RD, Kell WM, Sadik RA, Downs MB, Parker GW. Regulation of staphylococcal enterotoxin B-elicited nitric oxide production by endothelial cells. Infect Immunol. 1995;63:539–546.[Abstract]
24. Jordan NJ, Watson ML, Williams RJ, Roach AG, Yoshimura T, Westwick J. Chemokine production by human vascular smooth muscle cells: modulation by IL-13. Br J Pharmacol. 1997;122:749–757.[Medline] [Order article via Infotrieve]
25. Krakauer T. IL-10 inhibits the adhesion of leukocytic cells to IL-1-activated human endothelial cells. Immunol Lett. 1995;45:61–65.[Medline] [Order article via Infotrieve]
26. Van Der Meeren A, Squiban C, Gourmelon P, Lafont H, Gaugler MH. Differential regulation by IL-4 and IL-10 of radiation-induced IL-6 and IL-8 production and ICAM-1 expression by human endothelial cells. Cytokine. 1999;11:831–838.[Medline] [Order article via Infotrieve]
27. Selzman CH, Meldrum DR, Cain BS, Meng X, Shames BD, Ao L, Harken AH. Interleukin-10 inhibits postinjury tumor necrosis factor-mediated human vascular smooth muscle proliferation. J Surg Res. 1998;80:352–356.[Medline] [Order article via Infotrieve]
28.
Peilot H,
Rosengren B, Bondjers G, Hurt-Camejo E. Interferon- induces
secretory group IIA phospholipase A2 in human arterial
smooth muscle cells: involvement of cell differentiation, STAT-3
activation, and modulation by other cytokines.
J Biol Chem. 2000;275:22895–22904.
29.
Pinderski Oslund
LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA, Fyfe
AI. Interleukin-10 blocks atherosclerotic events in vitro and in vivo.
Arterioscler Thromb Vasc Biol. 1999;19:2847–2853.
30.
Mallat Z, Deleuze
V, Merval R, Bureau MF, Esposito B, Duverger N, Scherman D, Tedgui A.
In vivo electrotransfer of interleukin-10 prevents diet-induced
endothelial NF-B activation and expression of
adhesion molecules.
Circulation. 2000;102:II-115.
Abstract.
31. Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW. Expression cloning and characterization of a human IL-10 receptor. J Immunol. 1994;152:1821–1829.[Abstract]
32.
Spencer SD, Di
Marco F, Hooley J, Pitts-Meek S, Bauer M, Ryan AM, Sordat B, Gibbs VC,
Aguet M. The orphan receptor CRF2–4 is an essential subunit of the
interleukin 10 receptor. J Exp
Med. 1998;187:571–578.
33.
Riley JK, Takeda
K, Akira S, Schreiber RD. Interleukin-10 receptor signaling through the
JAK-STAT pathway: requirement for two distinct receptor-derived signals
for anti-inflammatory action. J Biol
Chem. 1999;274:16513–16521.
34.
Schottelius AJ,
Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks
inhibitor of B kinase activity and nuclear factor B
DNA binding. J Biol Chem. 1999;274:31868–31874.
35.
Suttles J,
Milhorn DM, Miller RW, Poe JC, Wahl LM, Stout RD. CD40 signaling of
monocyte inflammatory cytokine synthesis through an
ERK1/2-dependent pathway: a target of interleukin (IL)-4 and IL-10
anti-inflammatory action. J Biol
Chem. 1999;274:5835–5842.
36.
Kishore R, Tebo
JM, Kolosov M, Hamilton TA. Cutting edge: clustered AU-rich elements
are the target of IL-10-mediated mRNA destabilization in mouse
macrophages. J
Immunol. 1999;162:2457–2461.
37. Mulligan MS, Jones ML, Vaporciyan AA, Howard MC, Ward PA. Protective effects of IL-4 and IL-10 against immune complex-induced lung injury. J Immunol. 1993;151:5666–5674.[Abstract]
38.
Downing LJ,
Strieter RM, Kadell AM, Wilke CA, Austin JC, Hare BD, Burdick MD,
Greenfield LJ, Wakefield TW. IL-10 regulates thrombus-induced vein wall
inflammation and thrombosis. J
Immunol. 1998;161:1471–1476.
39. Morise Z, Eppihimer M, Granger DN, Anderson DC, Grisham MB. Effects of lipopolysaccharide on endothelial cell adhesion molecule expression in interleukin-10 deficient mice. Inflammation. 1999;23:99–110.[Medline] [Order article via Infotrieve]
40.
Henke PK,
DeBrunye LA, Strieter RM, Bromberg JS, Prince M, Kadell AM, Sarkar M,
Londy F, Wakefield TW. Viral IL-10 gene transfer decreases inflammation
and cell adhesion molecule expression in a rat model of venous
thrombosis. J Immunol. 2000;164:2131–2141.
41.
Pugin J, Ulevitch
RJ, Tobias PS. A critical role for monocytes and CD14 in
endotoxin-induced endothelial cell activation.
J Exp Med. 1993;178:2193–2200.
42.
Mallat Z, Heymes
C, Ohan J, Faggin E, Lesèche G, Tedgui A. Expression of
interleukin-10 in human atherosclerotic plaques: relation to inducible
nitric oxide synthase expression and cell death.
Arterioscler Thromb Vasc Biol. 1999;19:611–616.
43. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999;85:e17–e24.
44. Hayward R, Nossuli TO, Scalia R, Lefer AM. Cardioprotective effect of interleukin-10 in murine myocardial ischemia-reperfusion. Eur J Pharmacol. 1997;334:157–163.[Medline] [Order article via Infotrieve]
45. Santucci L, Fiorucci S, Chiorean M, Brunori PM, Di Matteo FM, Sidoni A, Migliorati G, Morelli A. Interleukin 10 reduces lethality and hepatic injury induced by lipopolysaccharide in galactosamine-sensitized mice. Gastroenterology. 1996;111:736–744.[Medline] [Order article via Infotrieve]
46.
Frangogiannis NG,
Mendoza LH, Lindsey ML, Ballantyne CM, Michael LH, Smith CW, Entman ML.
IL-10 is induced in the reperfused myocardium and may
modulate the reaction to injury. J
Immunol. 2000;165:2798–2808.
47. Uyemura K, Demer LL, Castle SC, Jullien D, Berliner JA, Gately MK, Warrier RR, Pham N, Fogelman AM, Modlin RL. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest. 1996;97:2130–2138.[Medline] [Order article via Infotrieve]
48.
Feldman LJ,
Aguirre L, Ziol M, Bridou JP, Nevo N, Michel JB, Steg PG.
Interleukin-10 inhibits intimal hyperplasia after angioplasty or stent
implantation in hypercholesterolemic rabbits.
Circulation. 2000;101:908–916.
49.
Gunnett CA,
Heistad DD, Berg DJ, Faraci FM. IL-10 deficiency increases superoxide
and endothelial dysfunction during inflammation.
Am J Physiol Heart Circ
Physiol. 2000;279:H1555–H1562.
50. Beasley D, Mcguiggin ME, Dinarello CA. Human vascular smooth muscle cells produce an intracellular form of interleukin-1 receptor antagonist. Am J Physiol Cell Physiol. 1995;38:C961–C968.
51.
Dewberry R,
Holden H, Crossman D, Francis S. Interleukin-1 receptor
antagonist expression in human endothelial
cells and atherosclerosis.
Arterioscler Thromb Vasc Biol. 2000;20:2394–2400.
52.
Elhage R, Maret
A, Pieraggi MT, Thiers JC, Arnal JF, Bayard F. Differential effects of
interleukin-1 receptor antagonist and tumor necrosis factor
binding protein on fatty-streak formation in apolipoprotein
E–deficient mice. Circulation. 1998;97:242–244.
53.
Nicklin MJ,
Hughes DE, Barton JL, Ure JM, Duff GW. Arterial
inflammation in mice lacking the interleukin 1 receptor
antagonist gene. J Exp
Med. 2000;191:303–312.
54.
Francis SE, Camp
NJ, Dewberry RM, Gunn J, Syrris P, Carter ND, Jeffery S, Kaski JC,
Cumberland DC, Duff GW, Crossman DC. Interleukin-1 receptor
antagonist gene polymorphism and coronary
artery disease. Circulation. 1999;99:861–866.
55.
Galea P, Thibault
G, Lacord M, Bardos P, Lebranchu Y. Il-4, but not tumor necrosis
factor-, increases endothelial cell adhesiveness for
lymphocytes by activating a cAMP-dependent pathway.
J Immunol. 1993;151:588–596.[Abstract]
56. Bochner BS, Klunk DA, Sterbinsky SA, Coffman RL, Schleimer RP. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol. 1995;154:799–803.[Abstract]
57.
Fukushi J, Ono M,
Morikawa W, Iwamoto Y, Kuwano M. The activity of soluble VCAM-1 in
angiogenesis stimulated by IL-4 and IL-13.
J Immunol. 2000;165:2818–2823.
58. Ruetten H, Thiemermann C. Interleukin-13 is a more potent inhibitor of the expression of inducible nitric oxide synthase in smooth muscle cells than in macrophages: a comparison with interleukin-4 and interleukin-10. Shock. 1997;8:409–414.[Medline] [Order article via Infotrieve]
59.
George J,
Shoenfeld Y, Gilburd B, Afek A, Shaish A, Harats D. Requisite role for
interleukin-4 in the acceleration of fatty streaks induced by heat
shock protein 65 or Mycobacterium tuberculosis.
Circ Res. 2000;86:1203–1210.
60.
Zwacka RM, Zhou
W, Zhang Y, Darby CJ, Dudus L, Halldorson J, Oberley L, Engerlhardt JF.
Redox gene therapy for ischaemia/reperfusion injury of the liver
reduces AP-1 and NF-B activation. Nat
Med. 1998;4:698–704.[Medline]
[Order article via Infotrieve]
61.
Ashby DT, Rye KA,
Clay MA, Vadas MA, Gamble JR, Barter PJ. Factors influencing the
ability of HDL to inhibit expression of vascular cell adhesion
molecule-1 in endothelial cells.
Arterioscler Thromb Vasc Biol. 1998;18:1450–1455.
62.
Cockerill GW,
Saklatvala J, Ridley SH, Yarwood H, Miller NE, Oral B, Nithyanathan S,
Taylor G, Haskard DO. High-density lipoproteins differentially modulate
cytokine-induced expression of E-selectin and
cyclooxygenase-2.
Arterioscler Thromb Vasc Biol. 1999;19:910–917.
63.
Baker PW, Rye KA,
Gamble JR, Vadas MA, Barter PJ. Ability of reconstituted high density
lipoproteins to inhibit cytokine-induced expression of
vascular cell adhesion molecule-1 in human umbilical vein
endothelial cells. J Lipid
Res. 1999;40:345–353.
64.
Cockerill GW,
Huehns TY, Weerasinghe A, Stocker C, Lerch PG, Miller NE, Haskard DO.
Elevation of plasma high-density lipoprotein concentration reduces
interleukin-1–induced expression of E-selectin in an in vivo model of
acute inflammation.
Circulation. 2001;103:108–112.
65.
Xia P, Vadas MA,
Rye KA, Barter PJ, Gamble JR. High density lipoproteins (HDL) interrupt
the sphingosine kinase signaling pathway: a possible mechanism for
protection against atherosclerosis by HDL.
J Biol Chem. 1999;274:33143–33147.
66.
Vinals M,
Martinez-Gonzalez J, Badimon L. Regulatory effects of HDL on smooth
muscle cell prostacyclin release.
Arterioscler Thromb Vasc Biol. 1999;19:2405–2411.
67. Dimayuga P, Zhu J, Oguchi S, Chyu KY, Xu XO, Yano J, Shah PK, Nilsson J, Cercek B. Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoE null mice. Biochem Biophys Res Commun. 1999;264:465–468.[Medline] [Order article via Infotrieve]
68.
Zachary I, Mathur
A, Yla-Herttuala S, Martin J. Vascular protection: a novel
nonangiogenic cardiovascular role for vascular
endothelial growth factor.
Arterioscler Thromb Vasc Biol. 2000;20:1512–1520.
69.
He H, Venema VJ,
Gu X, Venema RC, Marrero MB, Caldwell RB. Vascular
endothelial growth factor signals
endothelial cell production of nitric oxide and
prostacyclin through flk-1/KDR activation of c-Src.
J Biol Chem. 1999;274:25130–25135.
70.
Gamble JR, Drew
J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos
G, Vadas MA. Angiopoietin-1 is an antipermeability and
anti-inflammatory agent in vitro and targets cell junctions.
Circ Res. 2000;87:603–607.
71.
Willam C, Koehne
P, Jurgensen JS, Grafe M, Wagner KD, Bachmann S, Frei U, Eckardt KU.
Tie2 receptor expression is stimulated by hypoxia and
proinflammatory cytokines in human endothelial
cells. Circ Res. 2000;87:370–377.
72.
Pendurthi UR,
Williams JT, Rao LV. Acidic and basic fibroblast growth factors
suppress transcriptional activation of tissue factor and other
inflammatory genes in endothelial cells.
Arterioscler Thromb Vasc Biol. 1997;17:940–946.
73. Minter AJ, Keoshkerian E, Chesterman CN, Dawes J. Fibroblast growth factor and heparin protect endothelial cells from the effects of interleukin 1. J Cell Physiol. 1996;167:229–237.[Medline] [Order article via Infotrieve]
74.
Hla T, Maciag T.
Cyclooxygenase gene expression is down-regulated by
heparin-binding (acidic fibroblast) growth factor-1 in human
endothelial cells. J
Biol Chem. 1991;266:24059–24063.
75.
Corseaux D,
Meurice T, Six I, Rugeri L, Ezekowitz MD, Rouvier P, Bordet R, Bauters
C, Jude B. Basic fibroblast growth factor increases tissue factor
expression in circulating monocytes and in vascular wall.
Circulation. 2000;101:2000–2006.
76.
Bogdanov VY, Poon
M, Taubman MB. Platelet-derived growth factor-specific regulation
of the JE promoter in rat aortic smooth muscle cells.
J Biol Chem. 1998;273:24932–24938.
77. Morisaki N, Takahashi K, Shiina R, Zenibayashi M, Otabe M, Yoshida S, Saito Y. Platelet-derived growth factor is a potent stimulator of expression of intercellular adhesion molecule-1 in human arterial smooth muscle cells. Biochem Biophys Res Commun. 1994;200:612–618.[Medline] [Order article via Infotrieve]
78.
Scott-Burden T,
Schini VB, Elizondo E, Junquero DC, Vanhoutte PM. Platelet-derived
growth factor suppresses and fibroblast growth factor enhances
cytokine-induced production of nitric oxide by
cultured smooth muscle cells. Effects on cell proliferation.
Circ Res. 1992;71:1088–1100.
79.
de Martin R,
Hoeth M, Hofer-Warbinek R, Schmid JA. The transcription factor NF-B
and the regulation of vascular cell function.
Arterioscler Thromb Vasc Biol. 2000;20:E83–E88.
80.
Yamaoka S,
Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ,
Israel A. Complementation cloning of NEMO, a component of the IB
kinase complex essential for NF-B activation.
Cell. 1998;93:1231–1240.[Medline]
[Order article via Infotrieve]
81.
Janssen-Heininger
YM, Poynter ME, Baeuerle PA. Recent advances towards understanding
redox mechanisms in the activation of nuclear factor B.
Free Radic Biol Med. 2000;28:1317–1327.[Medline]
[Order article via Infotrieve]
82.
Gao Y, Lecker S,
Post MJ, Hietaranta AJ, Li J, Volk R, Li M, Sato K, Saluja AK, Steer
ML, Goldberg AL, Simons M. Inhibition of ubiquitin-proteasome
pathway-mediated IB degradation by a naturally occurring
antibacterial peptide. J Clin
Invest. 2000;106:439–448.[Medline]
[Order article via Infotrieve]
83.
May MJ,
D’Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S. Selective
inhibition of NF-B activation by a peptide that blocks the
interaction of NEMO with the IB kinase complex.
Science. 2000;289:1550–1554.
84.
Cooper JT, Stroka
DM, Brostjan C, Palmetshofer A, Bach FH, Ferran C. A20 blocks
endothelial cell activation through a NF-B-dependent
mechanism. J Biol Chem. 1996;271:18068–18073.
85.
Ferran C, Stroka
DM, Badrichani AZ, Cooper JT, Wrighton CJ, Soares M, Grey ST, Bach FH.
A20 inhibits NF-B activation in endothelial cells
without sensitizing to tumor necrosis factor-mediated
apoptosis. Blood. 1998;91:2249–2258.
86.
Stroka DM,
Badrichani AZ, Bach FH, Ferran C. Overexpression of A1, an
NF-B-inducible anti-apoptotic Bcl gene, inhibits
endothelial cell activation.
Blood. 1999;93:3803–3810.
87. Bach FH, Ferran C, Hechenleitner P, Mark W, Koyamada N, Miyatake T, Winkler H, Badrichani A, Candinas D, Hancock WW. Accommodation of vascularized xenografts: expression of "protective genes" by donor endothelial cells in a host Th2 cytokine environment. Nat Med. 1997;3:196–204.[Medline] [Order article via Infotrieve]
88.
Lee EG, Boone DL,
Chai S, Libby SL, Chien M, Lodolce JP, Ma A. Failure to regulate
TNF-induced NF-B and cell death responses in A20-deficient mice.
Science. 2000;289:2350–2354.
89. Willis D, Moore AR, Frederick R, Willoughby DA. Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med. 1996;2:87–90.[Medline] [Order article via Infotrieve]
90.
Terry CM,
Clikeman JA, Hoidal JR, Callahan KS. Effect of tumor necrosis
factor- and interleukin-1 on heme oxygenase-1
expression in human endothelial cells.
Am J Physiol. 1998;274:H883–H891.
91. Otterbein LE, Kolls JK, Mantell LL, Cook JL, Alam J, Choi AM. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest. 1999;103:1047–1054.[Medline] [Order article via Infotrieve]
92. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129–135.[Medline] [Order article via Infotrieve]
93.
Sata M, Suhara T,
Walsh K. Vascular endothelial cells and smooth muscle
cells differ in expression of Fas and Fas ligand and in sensitivity to
Fas ligand-induced cell death: implications for vascular disease and
therapy. Arterioscler Thromb Vasc
Biol. 2000;20:309–316.
94. Sata M, Walsh K. Fas ligand-deficient mice display enhanced leukocyte infiltration and intima hyperplasia in flow-restricted vessels. J Mol Cell Cardiol. 2000;32:1395–1400.[Medline] [Order article via Infotrieve]
95.
Young JL, Sukhova
GK, Foster D, Kisiel W, Libby P, Schonbeck U. The serpin proteinase
inhibitor 9 is an endogenous
inhibitor of interleukin 1ß-converting enzyme (caspase-1)
activity in human vascular smooth muscle cells.
J Exp Med. 2000;191:1535–1544.
96.
Kubes P, Suzuki
M, Granger DN. Nitric oxide: an endogenous modulator of
leukocyte adhesion. Proc Natl Acad Sci
U S A. 1991;88:4651–4655.
97. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone M Jr, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–68.
98.
Peng HB,
Rajavashisth TB, Libby P, Liao JK. Nitric oxide inhibits
macrophage-colony stimulating factor gene transcription in
vascular endothelial cells.
J Biol Chem. 1995;270:17050–17055.
99.
Zeiher AM,
Fisslthaler B, Schrayutz B, Busse R. Nitric oxide modulates the
expression of monocyte chemoattractant protein 1 in cultured human
endothelial cells. Circ
Res. 1995;76:980–986.
100.
Tsao PS, Wang
B, Buitrago R, Shyy JY, Cooke JP. Nitric oxide regulates monocyte
chemotactic protein-1.
Circulation. 1997;96:934–940.
101.
Shin WS, Hong
YH, Peng HB, Decaterina R, Libby P, Liao JK. Nitric oxide attenuates
vascular smooth muscle cell activation by interferon-: the role of
constitutive NF-B activity. J Biol
Chem. 1996;271:11317–11324.
102.
Spiecker
M, Peng HB, Liao JK. Inhibition of endothelial vascular
cell adhesion molecule-1 expression by nitric oxide involves the
induction and nuclear translocation of IB.
J Biol Chem. 1997;272:30969–30974.
103.
Luvara G, Pueyo
ME, Philippe M, Mandet C, Savoie F, Henrion D, Michel JB. Chronic
blockade of NO synthase activity induces a proinflammatory
phenotype in the arterial wall: prevention by
angiotensin II antagonism.
Arterioscler Thromb Vasc Biol. 1998;18:1408–1416.
104.
Kitamoto S,
Egashira K, Kataoka C, Koyanagi M, Katoh M, Shimokawa H, Morishita R,
Kaneda Y, Sueishi K, Takeshita A. Increased activity of nuclear
factor-B participates in cardiovascular remodeling
induced by chronic inhibition of nitric oxide synthesis in rats.
Circulation. 2000;102:806–812.
105.
Koyanagi M,
Egashira K, Kitamoto S, Ni W, Shimokawa H, Takeya M, Yoshimura T,
Takeshita A. Role of monocyte chemoattractant protein-1 in
cardiovascular remodeling induced by chronic blockade
of nitric oxide synthesis.
Circulation. 2000;102:2243–2248.
106.
Gonzalez W,
Fontaine V, Pueyo ME, Laquay N, Messika-Zeitoun D, Philippe M, Arnal
JF, Jacob MP, Michel JB. Molecular plasticity of vascular wall during
NG-nitro-L-arginine
methyl ester-induced hypertension: modulation of proinflammatory
signals. Hypertension. 2000;36:103–109.
107.
Usui M,
Egashira K, Tomita H, Koyanagi M, Katoh M, Shimokawa H, Takeya M,
Yoshimura T, Matsushima K, Takeshita A. Important role of local
angiotensin II activity mediated via type 1 receptor in the
pathogenesis of cardiovascular inflammatory changes
induced by chronic blockade of nitric oxide synthesis in rats.
Circulation. 2000;101:305–310.
108. Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol. 2000;129:823–834.[Medline] [Order article via Infotrieve]
109.
Delerive P,
Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez
P, Staels B. Peroxisome proliferator-activated receptor
activators inhibit thrombin-induced endothelin-1
production in human vascular endothelial cells
by inhibiting the activator protein-1 signaling pathway.
Circ Res. 1999;85:394–402.
110.
Marx N,
Bourcier T, Sukhova GK, Libby P, Plutzky J. PPAR activation in human
endothelial cells increases plasminogen
activator inhibitor type-1 expression: PPAR
as a potential mediator in vascular disease.
Arterioscler Thromb Vasc Biol. 1999;19:546–551.
111.
Staels B,
Koenig W, Habib A, Merval R, Lebret M, Pineda-Torra I, Delerive P,
Fadel A, Chinetti G, Fruchart J-C, Najib J, Maclouf J, Tedgui A.
Activation of human aortic smooth-muscle cells is inhibited by PPAR
but not by PPAR activators.
Nature. 1998;393:790–793.[Medline]
[Order article via Infotrieve]
112.
Marx N,
Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome
proliferator-activated receptor activators
inhibit gene expression and migration in human vascular smooth muscle
cells. Circ Res. 1998;83:1097–1103.
113.
Delerive P, De
Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ,
Fruchart JC, Tedgui A, Haegeman G, Staels B. Peroxisome
proliferator-activated receptor negatively regulates the
vascular inflammatory gene response by negative cross-talk with
transcription factors NF-B and AP-1.
J Biol Chem. 1999;274:32048–32054.
114.
Ricote M, Huang
J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W,
Glass CK. Expression of the peroxisome proliferator-activated
receptor (PPAR) in human atherosclerosis and
regulation in macrophages by colony stimulating factors and
oxidized low density lipoprotein. Proc
Natl Acad Sci
U S A. 1998;95:7614–7619.
115.
Marx N, Sukhova
G, Murphy C, Libby P, Plutzky J. Macrophages in human
atheroma contain PPAR: differentiation-dependent
peroxisomal proliferator-activated receptor (PPAR)
expression and reduction of MMP-9 activity through PPAR activation
in mononuclear phagocytes in vitro.
Am J Pathol. 1998;153:17–23.
116.
Chinetti G,
Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J,
Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B. CLA-1/SR-BI is
expressed in atherosclerotic lesion macrophages and regulated
by activators of peroxisome proliferator-activated
receptors. Circulation. 2000;101:2411–2417.
117.
Ricote M, Li
AC, Willson TM, Kelly CJ, Glass CK. The peroxisome
proliferator-activated receptor- is a negative regulator of
macrophage activation.
Nature. 1998;391:79–82.[Medline]
[Order article via Infotrieve]
118.
Jiang C, Ting
AT, Seed B, PPAR- agonists inhibit production of monocyte
inflammatory cytokines.
Nature. 1998;391:82–86.[Medline]
[Order article via Infotrieve]
119.
Marx N, Sukhova
GK, Collins T, Libby P, Plutzky J. PPAR activators
inhibit cytokine-induced vascular cell adhesion molecule-1
expression in human endothelial cells.
Circulation. 1999;99:3125–3131.
120.
Devchand PR,
Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The
PPAR-leukotriene B4 pathway to inflammation control.
Nature. 1996;384:39–43.[Medline]
[Order article via Infotrieve]
121. Klucis E, Crane D, Masters C. Sequential alterations in the micro-localization of catalase in mouse liver after treatment with hypolipidemic drugs. Mol Cell Biochem. 1984;65:73–82.[Medline] [Order article via Infotrieve]
122.
Delerive P,
Gervois P, Fruchart JC, Staels B. Induction of IB expression as a
mechanism contributing to the anti-inflammatory activities of
peroxisome proliferator-activated receptor-
activators. J Biol
Chem. 2000;275:36703–36707.
123.
De Caterina R,
Bernini W, Carluccio MA, Liao JK, Libby P. Structural requirements for
inhibition of cytokine-induced endothelial
activation by unsaturated fatty acids. J
Lipid Res. 1998;39:1062–1070.
124.
Wang BY, Ho HK,
Lin PS, Schwarzacher SP, Pollman MJ, Gibbons GH, Tsao PS, Cooke JP.
Regression of atherosclerosis: role of nitric oxide and
apoptosis. Circulation. 1999;99:1236–1241.
125.
Rubins HB,
Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E,
Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the
secondary prevention of coronary heart disease in men with low
levels of high-density lipoprotein cholesterol: Veterans
Affairs High-Density Lipoprotein Cholesterol Intervention
Trial Study Group. N Engl J
Med. 1999;341:410–418.
126. Gimbrone MA, Nagel T, Topper JN. Biomechanical activation: an emerging paradigm in endothelial adhesion biology. J Clin Invest. 1997;99:1809–1813.[Medline] [Order article via Infotrieve]
127.
Davies PF.
Flow-mediated endothelial mechanotransduction.
Physiol Rev. 1995;75:519–560.
128. Sampath R, Kukielka GL, Smith CW, Eskin SG, Mcintire LV. Shear stress-mediated changes in the expression of leukocyte adhesion receptors on human umbilical vein endothelial cells in vitro. Ann Biomed Eng. 1995;23:247–256.[Medline] [Order article via Infotrieve]
129.
Mohan S, Mohan
N, Valente AJ, Sprague EA. Regulation of low shear flow-induced HAEC
VCAM-1 expression and monocyte adhesion.
Am J Physiol. 1999;276:C1100–C1107.
130.
Chappell DC,
Varner SE, Nerem RM, Medford RM, Alexander RW. Oscillatory shear stress
stimulates adhesion molecule expression in cultured human
endothelium. Circ
Res. 1998;82:532–539.
131. Hsiai TK, Sung CK, Susan HY, Jin LS, Honda H, Reddy ST, Navab M, Fogelman AM, Demer L. Pulsatile vs oscillatory flow profiles have opposite effects on monocyte adhesion to ox-PAPC treated endothelial cells. Circulation. 2000;102:II-185. Abstract.
132.
Walpola PL,
Gotlieb AI, Cybulsky MI, Langille BL. Expression of ICAM-1 and VCAM-1
and monocyte adherence in arteries exposed to altered shear stress.
Arterioscler Thromb Vasc Biol. 1995;15:2–10.
133.
Hajra L, Evans
AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-B signal
transduction pathway in aortic endothelial cells is
primed for activation in regions predisposed to atherosclerotic lesion
formation. Proc Natl Acad Sci
U S A. 2000;97:9052–9057.
134.
Inoue N,
Ramasamy S, Fukai T, Nerem RM, Harrison DG. Shear stress modulates
expression of Cu/Zn superoxide dismutase in human aortic
endothelial gels. Circ
Res. 1996;79:32–37.
135.
Dimmeler S,
Hermann C, Galle J, Zeiher AM. Upregulation of superoxide dismutase and
nitric oxide synthase mediates the apoptosis-suppressive
effects of shear stress on endothelial cells.
Arterioscler Thromb Vasc Biol. 1999;19:656–664.
136.
De Keulenaer
GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK.
Oscillatory and steady laminar shear stress differentially affect human
endothelial redox state: role of a superoxide-producing
NADH oxidase. Circ Res. 1998;82:1094–1101.
137. Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6:593–597.[Medline] [Order article via Infotrieve]
138. Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK): from inflammation to development. Curr Opin Cell Biol. 1998;10:205–219.[Medline] [Order article via Infotrieve]
139. Hoefen RJ, Berk BC. Shear stress inhibits interleukin-1ß–induced activation of JNK but not p38 in endothelial cells. Circulation. 2000;102:II-185. Abstract.
140.
Urbich C,
Fritzenwanger M, Zeiher AM, Dimmeler S. Laminar shear stress
upregulates the complement-inhibitory protein clusterin: a
novel potent defense mechanism against complement-induced
endothelial cell activation.
Circulation. 2000;101:352–355.
141. Urbich C, Mallat Z, Tedgui A, Zeiher A, Dimmeler S. Upregulation of the inhibitory adapter protein TRAF3 by shear stress blocks CD40-mediated endothelial cell activation. Circulation. 2000;102:II-115. Abstract.
142. Ridker PM. Inflammation, atherosclerosis, and cardiovascular risk: an epidemiologic view. Blood Coagul Fibrinolysis. 1999;10(suppl 1):S9–S12.
143.
Shi W,
Haberland ME, Jien ML, Shih DM, Lusis AJ. Endothelial
responses to oxidized lipoproteins determine genetic susceptibility to
atherosclerosis in mice.
Circulation. 2000;102:75–81.
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F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
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Z. Mallat, A. Gojova, V. Sauzeau, V. Brun, J.-S. Silvestre, B. Esposito, R. Merval, H. Groux, G. Loirand, and A. Tedgui Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice Circ. Res., October 31, 2003; 93(9): 884 - 888. [Abstract] [Full Text] [PDF]
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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 P. Meerarani, G. Reiterer, M. Toborek, and B. Hennig Zinc Modulates PPAR{gamma} Signaling and Activation of Porcine Endothelial Cells J. Nutr., October 1, 2003; 133(10): 3058 - 3064. [Abstract] [Full Text] [PDF]
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 B.-W. Wang, H. Chang, S. Lin, P. Kuan, and K.-G. Shyu Induction of matrix metalloproteinases-14 and -2 by cyclical mechanical stretch is mediated by tumor necrosis factor-{alpha} in cultured human umbilical vein endothelial cells Cardiovasc Res, August 1, 2003; 59(2): 460 - 469. [Abstract] [Full Text] [PDF]
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 K. Nuotio, P. J. Lindsberg, O. Carpen, L. Soinne, E. M.P. Lehtonen-Smeds, E. Saimanen, R. Lassila, T. Sairanen, S. Sarna, O. Salonen, et al. Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis Neurology, June 24, 2003; 60(12): 1890 - 1899. [Abstract] [Full Text] [PDF]
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 K. A. Nath, S. K. R. Kanakiriya, J. P. Grande, A. J. Croatt, and Z. S. Katusic Increased Venous Proinflammatory Gene Expression and Intimal Hyperplasia in an Aorto-Caval Fistula Model in the Rat Am. J. Pathol., June 1, 2003; 162(6): 2079 - 2090. [Abstract] [Full Text] [PDF]
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K. Esposito, A. Pontillo, F. Giugliano, G. Giugliano, R. Marfella, G. Nicoletti, and D. Giugliano Association of Low Interleukin-10 Levels with the Metabolic Syndrome in Obese Women J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1055 - 1058. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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N. Vila, J. Castillo, A. Davalos, A. Esteve, A. M. Planas, and A. Chamorro Levels of Anti-Inflammatory Cytokines and Neurological Worsening in Acute Ischemic Stroke Stroke, March 1, 2003; 34(3): 671 - 675. [Abstract] [Full Text] [PDF]
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F. M. Faraci Vascular Protection Stroke, February 1, 2003; 34(2): 327 - 329. [Full Text] [PDF]
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 G. A. Preston, C. S. Zarella, W. F. Pendergraft III, E. H. Rudolph, J. J. Yang, S. B. Sekura, J. C. Jennette, and R. J. Falk Novel Effects of Neutrophil-Derived Proteinase 3 and Elastase on the Vascular Endothelium Involve In Vivo Cleavage of NF-{kappa}B and Proapoptotic Changes in JNK, ERK, and p38 MAPK Signaling Pathways J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2840 - 2849. [Abstract] [Full Text] [PDF]
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F. Parhami, B. Basseri, J. Hwang, Y. Tintut, and L. L. Demer High-Density Lipoprotein Regulates Calcification of Vascular Cells Circ. Res., October 4, 2002; 91(7): 570 - 576. [Abstract] [Full Text] [PDF]
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Z. Mallat, J.-S. Silvestre, S. Le Ricousse-Roussanne, L. Lecomte-Raclet, A. Corbaz, M. Clergue, M. Duriez, V. Barateau, S. Akira, A. Tedgui, et al. Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Ischemia-Induced Neovascularization in Mice Hindlimb Circ. Res., September 6, 2002; 91(5): 441 - 448. [Abstract] [Full Text] [PDF]
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 C. M. Devlin, G. Kuriakose, E. Hirsch, and I. Tabas Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size PNAS, April 30, 2002; 99(9): 6280 - 6285. [Abstract] [Full Text] [PDF]
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F. M. Faraci Vascular Biology: Look What We Staggered Into Circ. Res., April 19, 2002; 90(7): 749 - 750. [Full Text] [PDF]
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S. I. McFarlane, R. Muniyappa, R. Francisco, and J. R. Sowers Pleiotropic Effects of Statins: Lipid Reduction and Beyond J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1451 - 1458. [Abstract] [Full Text] [PDF]
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 S. S. Cheng, N. W. Lukacs, and S. L. Kunkel Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells J. Immunol., March 15, 2002; 168(6): 2887 - 2894. [Abstract] [Full Text] [PDF]
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W. Erl and W. Siess Sphingosine-1-Phosphate and the Leading Edg-1 of Vascular Smooth Muscle Cells Circ. Res., September 14, 2001; 89(6): 474 - 476. [Full Text] [PDF]
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S. Besnard, J.-S. Silvestre, M. Duriez, J. Bakouche, Y. Lemaigre-Dubreuil, J. Mariani, B. I. Levy, and A. Tedgui Increased Ischemia-Induced Angiogenesis in the Staggerer Mouse, a Mutant of the Nuclear Receptor Ror{alpha} Circ. Res., December 7, 2001; 89(12): 1209 - 1215. [Abstract] [Full Text] [PDF]
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J.L. Mehta, H.J. Chen, and D.Y. Li Protection of Myocytes From Hypoxia-Reoxygenation Injury by Nitric Oxide Is Mediated by Modulation of Transforming Growth Factor-{beta}1 Circulation, May 7, 2002; 105(18): 2206 - 2211. [Abstract] [Full Text] [PDF]
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