| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 8, Number 12, December 2007
Contents
Murine Atherosclerosis (Part II)
Guest Editor: Godfrey S. Getz
Editorial Pp. 1221
Oxidative Stress as a Regulator of Murine Atherosclerosis
Pp. 1222-1229
T. Hsiai and J.A. Berliner
[Abstract]
The Toll of Toll-Like Receptors, Especially Toll-Like
Receptor 2, on Murine Atherosclerosis Pp. 1230-1238
L.K. Curtiss and P.S. Tobias
[Abstract]
Leukocyte Influx in Atherosclerosis Pp. 1239-1248
E. Galkina and K. Ley
[Abstract]
Macrophage-Derived Foam Cells in Atherosclerosis:
Lessons from Murine Models and Implications for Therapy
Pp. 1249-1263
N.R. Webb and K.J. Moore
[Abstract]
Cytokines as Regulators of Atherosclerosis in Murine
Models Pp. 1264-1272
Z. Mallat and A. Tedgui
[Abstract]
Use of Mouse Models to Evaluate Roles of Nuclear Receptors
and their Ligands in the Pathogenesis and Treatment of Atherosclerosis
Pp. 1273-1287
A.C. Li and C.K. Glass
[Abstract]
Apoptosis and Efferocytosis in Mouse Models of Atherosclerosis
Pp. 1288-1296
I. Tabas
[Abstract]
The Immune System and Murine Atherosclerosis
Pp. 1297-1306
G.S. Getz, P.A. VanderLaan and C.A. Reardon
[Abstract]
Lipases as Modulators of Atherosclerosis in Murine
Models Pp. 1307-1319
R.J. Brown and D.J. Rader
[Abstract]
Abstracts
[Back to top]
Editorial
Atherosclerosis is a complex chronic inflammatory response
to lipoprotein dysfunction, especially in experimental animals.
It involves the modification and retention of lipoproteins
within the intima. This elicits an activation of the endothelium
resulting in upregulation of the expression of adhesion molecules
and chemokines, both of which promote the recruitment of monocytes.
Once in the intima, these monocytes are transformed to macrophages.
The macrophages are multi-functional cells that not only take
up a variety of modified lipoproteins to become foam cells,
but also exert complex pro- and anti-inflammatory influences,
mediated mostly by the secretion of cytokines but also by
cell-cell interactions. Also recruited to the intima are a
variety of subsets of T cells that are capable of influencing
macrophage biology and are themselves influenced by the macrophages.
Many of the monocytes/macrophages undergo apoptosis, which
if not removed by efficient phagocytosis creates a body of
secondary necrotic cells responsible for the necrotic core
of advanced atherosclerotic lesions. The crosstalk between
the major cell participants in atherogenesis sets up a very
complex set of local interactions. The complexity of these
interactions is reflected in the very large number of manipulations
that are capable of exerting substantial effects on experimental
atherosclerosis. Each of these stages of atherogenesis is
explored in the reviews that follow.
In the first issue devoted to murine atherogenesis, we focused
on the variety of risk factors that might impact on mouse
atherosclerotic lesion development. These included diet, genetics,
gender, hypertension, obesity, diabetes, acute inflammatory
markers, and metabolic syndrome. This second issue is devoted
to the exploration of mechanistic influences related to the
process of atherogenesis. Thus the relationship between oxidative
stress and atherogenesis is reviewed by Berliner and colleagues.
Lipoproteins when modified may activate toll-like receptors.
Their involvement in murine atherogenesis is reviewed by Tobias
and Curtiss. Brown and Rader review the biology of the three
lipase family members, lipoprotein lipase, hepatic lipase
and endothelial lipase. They influence atherosclerosis by
hydrolyzing lipoprotein lipids or by tethering lipoproteins
to cell surface proteoglycans and receptors The recruitment
of the cellular components, monocytes and T cells in particular,
to the evolving atherosclerotic plaque is discussed in detail
by Galkina and Ley. The uptake of modified lipoproteins and
storage of cholesterol esters is the subject of a review by
Moore and Webb, who also discuss cholesterol efflux from these
cells. The role of cytokines produced by the cellular participants
in the plaque is discussed by Mallat and Tedgui. They note
the participation of both pro-and anti-inflammatory cytokines
and also discuss in detail the involvement of regulatory T
cells. The phenotype of the macrophage of the lesion is possibly
influenced by the generation of intracellular sets of the
ligands that influence gene transcription. Their targets are
the nuclear hormone receptors, which are discussed extensively
by Li and Glass in their review. The number of macrophage
foam cells is the result the relative rates of recruitment,
egress and cell death. The latter is reviewed in detail by
Tabas. The local immune network that constitutes the atherosclerotic
lesion is reviewed by Getz, VanderLaan and Reardon. In the
third issue that will complete the series, various complications
of atherosclerosis and potential therapeutic approaches will
bring this extensive series on murine atherosclerosis to an
end.
Godfrey S. Getz
Department of Pathology
The University of Chicago
5841 S. Maryland Avenue
Chicago, IL 60637
USA
E-mail: getz@bsd.uchicago.edu
[Back to top]
Oxidative Stress as a Regulator of Murine Atherosclerosis
T. Hsiai and J.A. Berliner
Altered cellular production of reactive oxygen species (ROS)
and/or reactive nitrogen species (RNS) is a ubiquitous feature
of human disease. Vascular oxidative stress is a unifying
area of research in atherosclerosis and aging. While elevated
levels of ROS, especially oxygen radicals (O2-•)
and hydrogen peroxide (H2O2),
induce cellular apoptosis, low levels play an important role
in cell signaling [1,2]. Reactive species from a variety of
sources further play an important role in plaque disruption
partly through lipid oxidation, low-density lipoprotein oxidation
nitration, and signaling [3-6].
[Back to top]
The Toll of Toll-Like Receptors, Especially Toll-Like
Receptor 2, on Murine Atherosclerosis
L.K. Curtiss and P.S. Tobias
At one time, atherosclerosis was thought to be a simple lipid
storage disease. However, it is now recognized as a chronic
and progressive inflammation of the arterial wall. Gene deletion
experiments in murine models of atherosclerosis that reduce
the inflammatory process also reduce disease severity. Identifying
the initiators and mediators of that inflammation can provide
promising avenues for prevention or therapy. Two prominent
risk factors, hyperlipidemia and infectious disease, point
to innate immune mechanisms as potential contributors to proatherogenic
inflammation. The Toll-like receptors (TLR), proinflammatory
sensors of pathogens, are potential links between inflammation,
infectious disease and atherosclerosis. There is increasing
evidence that TLRs also recognize host-derived ligands and
this also connects TLRs to diseases that may not have an etiology
that is associated directly with infection. A mechanism for
hyperlipidemic initiation of sterile inflammation can be postulated
because oxidized lipoproteins or their component oxidized
lipids have been identified as TLR ligands. Moreover, infectious
agents are correlated with atherosclerosis risk. There are
multiple published reports that TLR4 activation is relevant
to the inflammation of atherosclerosis in mice and humans.
In addition, we have identified a role for TLR2 in atherosclerosis
in low density lipoprotein receptor-deficient (LDLr-/-) mice.
Proatherogenic TLR2 responses to unknown endogenous or unknown
endemic exogenous agonists are mediated by non-bone marrow-derived
cells, which can include endothelial cells, adventitial fibroblasts
and vascular smooth muscle cells. This is in contrast to the
proatherogenic TLR2 response to defined synthetic exogenous
agonists, which is mediated at least in part by bone marrow-derived
cells, which can include lymphocytes, monocytes/macrophages,
NK cells and dendritic cells. Thus, TLR2-mediated cell activation
in response to endogenous and exogenous agents is proatherogenic
in hyperlipidemic mice.
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Leukocyte Influx in Atherosclerosis
E. Galkina and K. Ley
Atherosclerosis is a chronic inflammatory disease of the arterial
wall and an increasing body of evidence suggests that the
immune system actively participates in the initiation, progression
and persistence of atherosclerosis. Different types of leukocytes
such as T and B lymphocytes, natural killer cells (NK) and
NKT cells, macrophages, dendritic cells and mast cells have
been found within atherosclerosis-prone aortas. The mechanisms
of monocyte recruitment have been partially characterized
and involve P-selectin, E-selectin, VCAM-1, ICAM-1 and JAM-A.
CXCL1, CCL5, CXCL4, CXCL7 and MIF are also implicated in monocyte
trafficking into aortas. Recently it has been reported that
Ly6Chigh and Ly6Clow
monocyte subsets differently use CCL2, CX3CL1 and CCL5 for
their homing into atherosclerotic aortas. T and B lymphocytes
constitutively migrate into the normal and atherosclerotic
aortic wall in an L-selectin-dependent manner. Recent studies
suggest an important role of CCL5, CXCL10, CXCL16, CXCR6 and
MIF in T cell influx into the atherosclerotic wall. However,
there is little information available on the mechanisms of
recruitment of other types of the immune cells such as NK,
NKT and mast cells. In this review we shall summarize what
is known about leukocyte recruitment into the aortic wall
during atherosclerosis with a focus on mouse model systems.
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Macrophage-Derived Foam Cells in Atherosclerosis:
Lessons from Murine Models and Implications for Therapy
N.R. Webb and K.J. Moore
Macrophage-derived foam cells play integral roles in all stages
of atherosclerosis. These lipid-laden immune cells are present
from the earliest discernable fatty-streak lesions to advanced
plaques, and are key regulators of the pathologic behavior
of plaques. This review summarizes the current understanding
of the molecular mechanisms that regulate macrophage cholesterol
uptake, foam cell formation, and lipid-driven pro-inflammatory
responses that promote atherosclerosis. Specific emphasis
will be placed on recent findings from mouse models of atherosclerosis
regarding the pathways of macrophage differentiation into
foam cells and their implications for developing macrophage-directed
therapeutic targets.
[Back to top]
Cytokines as Regulators of Atherosclerosis in Murine
Models
Z. Mallat and A. Tedgui
Atherosclerosis is a chronic inflammatory disease of the arterial
wall initiated by a variety of pro-atherogenic stimuli, such
as modified epitopes of phospholipids. Both innate and adaptive
immune responses contribute to disease initiation and progression.
Here, we review the major cytokines involved in this immuno-inflammatory
response, and shown to significantly impact disease initiation
and/or progression in murine models. We particularly emphasize
the role of the regulatory arm of the immune response in disease
modulation, and review the major factors that may be involved
in its promotion or alteration.
[Back to top]
Use of Mouse Models to Evaluate Roles of Nuclear Receptors
and their Ligands in the Pathogenesis and Treatment of Atherosclerosis
A.C. Li and C.K. Glass
Nuclear receptors form a large family of ligand-dependent
transcription factors that regulate diverse aspects of development
and homeostasis. Several of these receptors have been demonstrated
to play important roles in controlling biological processes
that influence the development and clinical consequences of
atherosclerosis. Because nuclear receptors are regulated by
small molecules, they are potential targets for anti-atherogenic
drugs. In this chapter, we review the use of mouse models
to evaluate roles of nuclear receptors and their ligands in
the pathogenesis and treatment of atherosclerosis.
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Apoptosis and Efferocytosis in Mouse Models of Atherosclerosis
I. Tabas
Throughout the process of atherosclerosis, lesional macrophages,
smooth muscle cells, and possibly endothelial cells undergo
programmed cell death, or apoptosis. Under normal physiologic
conditions, apoptotic cells are rapidly cleared by neighboring
phagocytes, a process called efferocytosis, which prevents
secondary cellular necrosis and inflammation. If efferocytosis
is not efficient, necrosis, inflammation, and tissue damage
ensue. Mouse models of atherosclerosis offer the best opportunity
to understand the mechanisms and consequences of lesional
cell apoptosis and efferocytosis in atherogenesis and plaque
progression. Studies in mice to date have suggested that properly
coupled macrophage apoptosis and efferocytosis in early atherosclerosis
limits lesion size. The results of other mouse studies suggest
that macrophage and smooth muscle cell apoptosis and defective
efferocytosis in advanced lesions promotes plaque necrosis.
Future insight into these critically important processes will
require additional insight into the molecular and cellular
mechanisms that lead to lesional cell apoptosis and efferocytosis
as well as new mouse models of plaque disruption and thrombosis.
Advances in these areas offer great hope for eventual translation
into innovative therapeutic strategies to combat atherothrombotic
vascular disease.
[Back to top]
The Immune System and Murine Atherosclerosis
G.S. Getz, P.A. VanderLaan and C.A. Reardon
In this review the modulation of lipoprotein metabolism and
atherogenesis by the innate and adaptive immune systems of
the mouse is discussed. While recognizing the participation
of all components of the immune system in atherogenesis, it
is clear that robust atherogenesis may proceed without an
adaptive immune response. But even when all components are
active, the outcome reflects a balance between pro- and anti-inflammatory
reactants and cells. This network of interactions is summarized
in this review and is complemented by other reviews in this
series. Also noted is the differential response of different
vascular beds following manipulation of the components of
the adaptive immune system. Further work is required to achieve
a fuller understanding of the role of these systems in atherogenesis,
especially with the prospect of favorably modulating atherogenesis
by the manipulation of the participating immune components
as for example in a vaccination approach.
[Back to top]
Lipases as Modulators of Atherosclerosis in Murine
Models
R.J. Brown and D.J. Rader
Lipoprotein lipase, hepatic lipase, and endothelial lipase
are sn-1 lipases that play important roles in the metabolism
of plasma lipoproteins. In vitro and in vivo
studies suggest that these lipases exhibit both pro- and anti-atherogenic
properties, which are dependent primarily on their tissue
localization. The following chapter reviews the physiology
of these lipases, and the consequences of the loss or gain
of function for each lipase in modulating atherosclerosis,
with emphasis on murine models.
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