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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 9, Number 3, March 2008
Contents
Murine Atherosclerosis (Part III)
Guest Editor: Godfrey S. Getz
Editorial Pp. 173
Lipoprotein Size and Susceptibility to Atherosclerosis
— Insights from Genetically Modified Mouse Models Pp.
174-189
M.M. Véniant, A.P. Beigneux, A. Bensadoun, L.G. Fong
and S.G. Young
[Abstract]
Natural Antibodies in Murine Atherosclerosis
Pp. 190-195
C.J. Binder, M-Y. Chou, L. Fogelstrand, K. Hartvigsen,
P.X. Shaw, A. Boullier and J.L. Witztum
[Abstract]
Atheroprotective Effects of HDL: Beyond Reverse
Cholesterol Transport Pp. 196-203
J.E. Feig, R. Shamir and E.A. Fisher
[Abstract]
Apo A-1 Mimetic Peptides as Atheroprotective Agents
in Murine Models Pp. 204-209
M. Navab, G.M. Anantharamaiah, S.T. Reddy, B.J. Van Lenten
and A.M. Fogelman
[Abstract]
Progression and Disruption of Advanced Atherosclerotic
Plaques in Murine Models Pp. 210-216
M.E. Rosenfeld, M.M. Averill, B.J. Bennett and S.M. Schwartz
[Abstract]
Myocardial Infarction Following Atherosclerosis
in Murine Models Pp. 217-223
A. Braun, A. Rigotti and B.L. Trigatti
[Abstract]
Murine Models of Atherosclerotic Calcification
Pp. 224-228
J.J. Hsu, Y. Tintut and L.L. Demer
[Abstract]
The Hemostasis System in Murine Atherosclerosis
Pp. 229-238
T. Iwaki, V.A. Ploplis and F.J. Castellino
[Abstract]
Vessel Graft Atherosclerosis in Murine Models Pp.
239-250
Y. Hu and Q. Xu
[Abstract]
Intimal Hyperplasia in Murine Models Pp.
251-260
D.Y. Hui
[Abstract]
Abstracts
[Back to top]
Editorial
In this comprehensive collection of reviews of various aspects
of atherosclerosis and atherosclerosis biology in mouse models,
the first issue dealt with risk factors such as diet, genetics,
gender, obesity, diabetes, hypertension, metabolic syndrome
and acute inflammation. The second issue was devoted to many
putative mechanisms contributing to atherosclerosis. Among
the topics reviewed were: the interaction of modified lipoproteins
with Toll-like receptors influencing atherosclerosis; the
role of oxidative stress in the stimulating atherogenesis;
the family of lipases (hepatic, lipoprotein, endothelial)
produced by a variety of atherosclerosis relevant cells and
capable of influencing lipoprotein homeostasis; the recruitment
of blood cells to the vessel wall during atherogenesis; the
central role of monocyte derived foam cells in atherosclerosis;
the cytokines produced by the variety of cell types among
innate and adaptive immune systems that influence atherosclerosis;
the role of nuclear receptors in regulating lipoprotein metabolism
and macrophage biology; the important effects of apoptosis
of cells of the atherosclerotic lesions particularly in influencing
the fate of these lesions; and the role of the adaptive immune
system in regulating lipoprotein homeostasis and atherogenesis.
In this the third and final issue of the journal devoted to
murine atherosclerosis, a variety of additional parameters
and potential complications of the atherosclerotic lesion
is examined in depth. First an extensive review by Veniant,
Beigneux, Bensadoun, Fong and Young is devoted to the influence
of lipoprotein size on atherosclerosis susceptibility as determined
from genetics studies. Modified lipoproteins that are thought
to play an important role in initiating the process of atherosclerosis
are also capable of serving as neoantigens, some of which
are also seen on the surface of apoptotic cells. The natural
antibodies to these neo-antigens are in evidence in atherosclerosis
models and may be useful markers of the oxidative aspects
of the life history of the atherosclerotic lesion. These antibodies
are discussed in detail in the review by Binder and Witztum.
The atherosclerotic lesion, despite its complexity and chronicity,
is nevertheless a dynamic lesion capable of being reversed
or modified particularly by the removal of its lipid content.
At least in the mouse, lesion reversibility is surprisingly
dynamic. HDL is an agent that affords a major atheroprotective
capacity via processes that extend beyond reverse cholesterol
transport. These processes are reviewed by Feig, Shamir and
Fisher. Based upon the notable atheroprotective and anti-inflammatory
properties of HDL, investigators have developed apolipoprotein
A-I small peptide mimetics that can be surprisingly effective
in reversing atherogenesis and can have other actions on vascular
pathobiology in mouse models. This story is reviewed by Navab,
Anantharamaiah, Reddy, Van Lenten and Fogelman. In human cardiovascular
biology, much attention is paid to the unstable plaque which
upon rupture provides a nidus for full thrombus formation
and obstruction of vascular channels. One of the limitations
of the murine models of atherosclerosis is the difficulty
of studying the unstable plaque upon which a thrombus supervenes.
However, Rosenfeld, Averill, Bennett and Schwartz have carefully
studied the advanced atherosclerotic lesion of apoE deficient
mice fed chow. They demonstrate complex lesions with intra-plaque
hemorrhage which apparently occurs over ruptured lateral fatty
streaks but does not result in occlusive thrombi. They warn
against regarding this as a model of the human ruptured plaque
which generally involves the fibrous cap and may be accompanied
by occlusive thrombi. Despite these observations, a fascinating
model of coronary thrombosis and myocardial infarction is
seen in the double knockout mouse involving apoE and SRB1
deficiency. Work with this model is carefully reviewed by
Braun, Rigotti and Trigatti. Other potential complications
of atherosclerosis may involve cartilaginous metaplasia and
calcification. These complications have been explored by Hsu,
Tintut, and Demer. Several investigators have studied the
role of proteins involved in hemostasis on atherogenesis.
In the light of the prominence of fibrin deposits and fibrin
degradation products in plaques, this topic has been reviewed
by Iwaki, Ploplis and Castellino. Surgical intervention with
organ transplantation and stenting of atherosclerotic lesions,
which involves injury to the plaque surface, may result in
blood vessel pathology, either arteriosclerosis or atherosclerosis.
This graft atherosclerosis is reviewed by Hu and Xu. Intimal
hyperplasia may be a feature of atherosclerosis, but injury
induced intimal hyperplasia is probably a separate entity
being dominated by proliferating smooth muscle cells. This
topic is expertly explored in the review by Hui.
This collection involving 28 separate reviews has extensively
explored currently available information on murine atherosclerosis
and related pathobiology. Represented in this collection are
the many faces of approaches to atherosclerosis from the initial
lesion to advanced and complicated plaques, from lipoprotein
homeostasis to lipid storage in lesions, from macrophages,
T cells and smooth muscle cells to advanced lesions containing
extracellular lipid and matrix proteins, from simple lipid
lesions to complex and varied lesion phenotypes. All of these
changes are influenced by the risk factors, diet, gender,
blood pressure and genetics. What emerges from this extensive
set of reviews is that we still have a great deal to learn
if we are to be able to therapeutically modify the fate of
lesions. This looms prominently on the horizon and further
studies of these models will undoubtedly reveal many surprises
and many opportunities. However one needs to hardly remind
oneself of the fact that as useful as murine models may be,
they do not accurately mimic what we see in pathologically
significant human atherosclerotic plaques. In the initial
overview introducing this collection of reviews I pointed
out some of the most obvious differences in atherosclerosis
relevant factors and phenotypes between mice and humans. The
study of human atherosclerosis remains the ultimate arbiter
for understanding the application of what we have learned
from the mouse models to the therapy of human vascular disease.
I am grateful to Dr Catherine A Reardon for her help with
this editorial.
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]
Lipoprotein Size and Susceptibility to Atherosclero —
Insights from Genetically Modified Mouse Models
M.M. Véniant, A.P. Beigneux, A. Bensadoun, L.G. Fong
and S.G. Young
High plasma levels of the apo-B–containing lipoproteins
are casually implicated in the pathogenesis of atherosclerosis.
This finding, backed by decades of animal and human studies,
has sparked interest in defining which classes of apo-B–containing
lipoprotein particles are most atherogenic. Although small
LDL particles and larger remnant lipoproteins both appear
to be atherogenic, it has been difficult to discern which
particles are the most atherogenic. Here, we summarize several
mouse models that have provided insights into this issue.
The influence of lipoprotein size on susceptibility to atherosclerosis
was examined by studying the phenotypes of two strains of
mice with virtually identical levels of plasma cholesterol—Ldlr
-/-
Apob 100/100
and Apoe -/-
Apob 100/100
mice. The Ldlr -/-
Apob 100/100
mice, where the cholesterol is in small LDL particles, had
far more atherosclerosis than Apoe -/-
Apob 100/100
mice, where virtually all of the cholesterol was in larger,
VLDL-sized particles. Another intriguing animal model is the
Gpihbp1-deficient mouse. GPIHBP1 is an endothelial
cell platform for lipolysis, and mice lacking this protein
have an accumulation of large, triglyceride-rich lipoproteins.
Defining the extent of atherosclerosis in these mice should
provide new insights into the atherogenicity of large, triglyceride-rich
lipoproteins.
[Back to top]
Natural Antibodies in Murine Atherosclerosis
C.J. Binder, M-Y. Chou, L. Fogelstrand, K. Hartvigsen,
P.X. Shaw, A. Boullier and J.L. Witztum
Natural antibodies are preformed antibodies that are
present even in naïve germ-free mice in the absence of
any exogenous antigenic exposure. Consistent with their specificities
for microbial antigens, natural antibodies play an important
non-redundant role in the first line defense against bacterial
and viral infections. On the other hand natural antibodies
have also been shown to have specificities for self antigens,
and therefore have been proposed to provide important homeostatic
“house-keeping” functions. Many of the recognized
self-antigens may in fact be stress-induced self-antigens,
such as oxidation-specific epitopes that accumulate during
atherogenesis as well as in many other inflammatory settings,
and natural antibodies could protect from the impact of the
pathological accumulation of these self-antigens. In this
review we will discuss the specific example of the prototypic
natural antibody T15/EO6, which is increased in atherosclerotic
mice and mediates atheroprotection, and discuss the potential
role of natural antibodies in atherogenesis in general.
[Back to top]
Atheroprotective Effects of HDL: Beyond Reverse Cholesterol
Transport
J.E. Feig, R. Shamir and E.A. Fisher
The risk of atherosclerosis is inversely related to circulating
levels of high density lipoprotein (HDL) cholesterol. Notably,
in large-scale epidemiologic studies, this association is
independent of plasma levels of low density lipoprotein cholesterol
levels. Pharmacologic agents, such as fibrates and niacin
that increase HDL cholesterol levels have been associated
with decreased cardiovascular events and beneficial effects
on the coronary and carotid arteries. Furthermore, there is
evidence that the risk of restenosis following vascular interventions
is inversely related to HDL levels. This review considers
the available data from mainly murine models on potential
mechanisms by which HDL may exert these anti-atherogenic effects,
namely through its role in reverse cholesterol transport,
its effects on endothelial cells, and its anti-inflammatory/anti-oxidant
activities. In addition to discussing a role for HDL in retarding
atherosclerosis progression, we will also review how HDL may
play a role in promoting regression of atherosclerotic lesions.
[Back to top]
Apo A-1 Mimetic Peptides as Atheroprotective Agents in Murine
Models
M. Navab, G.M. Anantharamaiah, S.T. Reddy, B.J. Van Lenten
and A.M. Fogelman
The mouse has proven to be an excellent model for testing
apolipoprotein mimetic peptides as agents to treat a variety
of vascular inflammatory conditions including atherosclerosis,
cognitive dysfunction associated with arteriole inflammation,
chronic rejection of transplanted hearts, and scleroderma.
The mechanism of action appears to relate to the ability of
these peptides to preferentially bind pro-inflammatory oxidized
lipids and is independent of the chirality of the peptides
since peptides synthesized from either D- or L-amino acids
appear to be equally effective.
[Back to top]
Progression and Disruption of Advanced Atherosclerotic Plaques
in Murine Models
M.E. Rosenfeld, M.M. Averill, B.J. Bennett and S.M. Schwartz
The innominate artery is a predilection site for atherosclerotic
lesion formation in hyperlipidemic mice. The lesions at this
site in chow-fed apo E-/- mice progress from fatty streaks
through stages that include atheroma with large necrotic areas,
fibro-fatty nodules containing chondrocyte-like cells and
highly calcified, acellular plaques. The advanced lesions
in the innominate arteries of the apo E-/- mice exhibit a
reproducible frequency of intra-plaque hemorrhage that occurs
primarily as a result of fissures through lateral fatty streaks
that form adjacent to or on top of the established plaques.
However, this plaque disruption is not equivalent to plaque
rupture in human lesions where there is rupture of well formed
fibrous caps. The plaque disruption in the lesions of the
chow-fed apo E-/- mice also do not lead to formation of occlusive
thrombi, the predominant marker of plaque rupture in humans.
Thus, although the lesions in the innominate arteries of hyperlipidemic
mice progress to very advanced stages of the disease, they
are not, in our opinion a model in which to study the mechanisms
of plaque rupture in humans. The advanced lesions in the innominate
arteries of the apo E-/- mice may however be adequate models
for studying vascular fibrosis and calcification.
[Back to top]
Myocardial Infarction Following Atherosclerosis in Murine
Models
A. Braun, A. Rigotti and B.L. Trigatti
The most widely used mouse models for atherosclerosis
are LDL receptor knockout (KO) mice and apolipoprotein E (apoE)
KO mice fed standard chow diets or lipid-supplemented diets.
Unfortunately, these do not usually exhibit myocardial infarction
or other features of human cardiovascular disease such as
occlusive coronary artery disease, cardiac dysfunction and/or
reduced lifespan. Surgical models of myocardial infarction
are successfully used for drug testing analyses during acute
ischemia, but do not allow investigation of underlying mechanisms
related to atherosclerotic coronary artery disease. Recently,
experts in the pharmaceutical industry as well as some at
the US Food and Drug Administration have identified inadequate
animal models as being one of the major hurdles in drug discovery
and development. There is an important need for additional
well-characterized, genetically manipulable, small animal
models that mimic many features of human coronary heart disease
(CHD), which would provide investigators in academia and in
the pharmaceutical industry with a better system to unravel
the pathophysiology of atherosclerotic CHD and to evaluate
pre-clinical drug candidates. Here we will review recently
developed mouse models of occlusive CHD, focusing on mice
lacking expression of the HDL receptor, SR-BI in the context
of reduced expression of apoE.
[Back to top]
Murine Models of Atherosclerotic Calcification
J.J. Hsu, Y. Tintut and L.L. Demer
Vascular calcification is associated with increased cardiovascular
morbidity and mortality and has long been associated with
advanced atherosclerotic lesions. While vascular calcification
is considered a surrogate marker for atherosclerosis, the
mechanisms that link the two are poorly understood. The consensus
of recent research is that active regulatory processes govern
vascular calcification, and much focus has been placed on
elucidating the phenomenon of atherosclerotic calcification.
Building upon extensive in vitro work and the previous
development of atherosclerotic murine models, several groups
have developed murine models of atherosclerotic calcification.
From imposing chronic renal failure to developing double-knockout
mice, this recent work has provided insight into the pathophysiology
of mineralized matrix formation in atherosclerotic lesions,
as well as development of potential therapies to prevent or
inhibit progression of calcified plaque. The aim is to briefly
review current understanding of the molecular basis for atherosclerotic
calcification and to discuss some murine models that may be
useful in advancing knowledge of its mechanisms.
[Back to top]
The Hemostasis System in Murine Atherosclerosis
T. Iwaki, V.A. Ploplis and F.J. Castellino
Atherosclerosis is a self-sustaining inflammatory fibroproliferative
disease that progresses in discrete stages and involves a
number of cell types and effector molecules. The potential
importance of the coagulation, anticoagulation, and fibrinolytic
systems in atherosclerosis is based on the observation that
fibrin deposits and fibrin degradation products are resident
in atherosclerotic plaques. A number of investigations have
been conducted to probe the relationships between components
of the hemostasis system and atherosclerosis; and these types
of studies proliferated after the availability of mice genetically
manipulated to emphasize the impact of genes of interest.
In order to summarize recent progress in this area, this review
is focused on mice lacking individual hemostasis genes and
their contributions to steps of the atherosclerotic process.
[Back to top]
Vessel Graft Atherosclerosis in Murine Models
Y. Hu and Q. Xu
The use of animal models in the study of arteriosclerosis
is essential for better understanding of the pathogenesis,
improvement in diagnosis, prevention and therapy of the diseases
in humans. Recently numerous investigators started to use
mouse models to study the pathogenesis of cardiovascular diseases.
This species is particularly valuable which is believed to
have some advantages over other strains, because of the availability
of well-defined genetic systems of transgenic and knockout
mice. Concomitantly, we have established the mouse models
for vein grafts and transplant arteriosclerosis. By using
these models, we have learned much knowledge concerning the
pathogenesis of the disease and possible therapeutic intervention
has been gained. One of most important findings is that proteins
or molecules influencing apoptosis, inflammation or proliferation
of vascular smooth muscle cells or endothelial cells, have
been found to enhance or inhibit neointimal lesion formation
in knockout or mutant mice in these models. Furthermore, the
findings on the origins of endothelial and smooth muscle cells
in lesions of vein graft and transplant atherosclerosis provided
basic information that have challenged the traditional hypothesies.
Using these models, it has also been demonstrated that stem
cells identified in blood and bone marrow as well as the vasculature
contribute to the atherosclerotic lesion formation, supporting
the importance of murine models of vessel grafts in understanding
the mechanisms of the vascular diseases. The present review
updates the progress of the research in this field, by summarizing
data of using mouse models of vessel grafts, and provides
a perspective analysis on the future directions.
[Back to top]
Intimal Hyperplasia in Murine Models
D.Y. Hui
The most commonly used procedures to induce arterial
injury in mice are carotid artery ligation with cessation
of blood flow and mechanically-induced denudation of endothelium
in the carotid or the femoral arteries. Both procedures result
in neointimal hyperplasia after two to three weeks. A survey
of various inbred strains of mice shows that strain-specific
differences in susceptibility to injury-induced neointimal
hyperplasia are different than those for susceptibility to
diet-induced atherosclerosis, with strains identified as susceptible
to both neointimal hyperplasia and atherosclerosis, resistant
to both, susceptible to atherosclerosis but resistant to neointimal
hyperplasia, or resistant to atherosclerosis but susceptible
to neointimal hyperplasia. Inflammatory cells such as T and
B lymphocytes, which are contributory to atherosclerosis,
are protective against injury-induced neointimal hyperplasia.
In contrast, the infiltration of monocytes into the site of
injury and their differentiation to macrophages favor neointimal
hyperplasia similar to their pathogenic role in atherosclerosis.
The regulatory role of lymphocytes and macrophages in neointimal
hyperplasia is related to the production of cytokines such
as interferon-γ
and tumor necrosis factor-α
, respectively. Interestingly, inducible nitric oxide synthase
(iNOS) activity appears to inhibit neointimal hyperplasia
in the endothelial denudation model but contributes to neointimal
hyperplasia when arterial injury is induced by periadventitial
cuff placement. The difference appears to be due to the time
required for endothelial recovery and the participation of
inflammatory cells. Thus, although arterial injury-induced
neointimal hyperplasia results in similar vascular occlusion
as progressive atherosclerosis, the pathology and mechanism
of the two disease processes are quite different.
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