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Editor

Prof. Jay L. Mehta

University of Arkansas for Medical Sciences
Division of Cardiovascular Disease
4301 West Markham
Mail Siot 532
Little Rock, AR 72205-7199
USA

A CIP catalogue record for this book is available from the Library of Congress, Washington D.C., USA

Deutsche Bibliothek Cataloging-in-Publication Data

Inflammatory and infectious basis of atherosclerosis / ed. by Jay L. Mehta. - Basel ; Boston; Berlin:
Birkhauser, 2001
(progress in inflammation research)
ISBN 978-3-0348-9487-6 ISBN 978-3-0348-8239-2 (eBook)
DOI 10.1007/978-3-0348-8239-2

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ISBN 978-3-0348-9487-6

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© 2001 Springer Basel AG
Originally published by Birkhauser Verlag in 2001
Softcover reprint of the hardcover 1st edition 2001
Printed on acid-free paper produced from chlorine-free pulp. TCF ~
Cover design: Markus Etterich, Basel
Cover illustration: Hypothetical sequence of evenls in atherosclerosis, advanced lesion. Ar! by John K. Richardson,
Medical Media Production Service, Malcom Randall VA Medical Center, Gainesville, Florida (chapter by Romeo et al.).

ISBN 978-3-0348-9487-6

987654321
Contents

List of contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. vii

Preface........................................................................... xi

Gerd Schmitz and Michael Torzewski

Atherosclerosis: an inflammatory disease 1

Renu Virmani, Frank D. Kolodgie, Allen P. Burke and Andrew Farb

Inflammation in coronary atherosclerosis - pathological aspects . . . . . . . . .. 23

Allard C. van der Wal, Onno J. de Boer and Anton E. Becker

Pathology of acute coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 47

Dani S. Zander
Transplantation-associated arteriosclerosis and inflammation . . . . . . . . . . . . . . . . . . .. 61

Heraldo P. Souza and Jay L. Zweier

Free radicals as mediators of inflammation in atherosclerosis. . . . . . . . . . . . . . . . . . .. 79

Keith A. Youker, Nikolaos Frangogiannis and Mark L. Entman

Myocardial reperfusion: a state of inflammation. ... . . . . . . . ... . . . . .. . . . . . . . . .. . .. 93

Mingyi Chen and Tatsuya Sawamura

LOX-1, a potential inflammatory mediator in atherosclerosis .................... 103

M. Ian Phillips, Shuntaro Kagiyama, Hongjiang Chen and

Jay L. Mehta
AngiotenSin II as a mediator of inflammation in atherosclerosis ................. 113
Contents

Bernhard Schieffer and Helmut Drexler

Role of interleukins in relation to the renin-angiotensin-system
in atherosclerosis ................................................. . . 129

Anupam Agarwal, Nathalie Hill-Kapturczak and Harry S. Nick

Heme oxygenase-1, inflammation and atherosclerosis. . ................. 141

Stefano De Servi and Antonino Mazzone

Lymphocyte activation in acute coronary syndromes ............................ 159

Francesco Romeo, Fabrizio Clementi, Tom Saldeen and Jay L. Mehta

Role of infection in atherosclerosis and precipitation of
acute cardiac events ............................................................. 185

David A. Morrow and Paul M. Ridker

C-reactive protein - a prognostic marker of inflammation in
atherothrombosis ............................................. . ................ 203

Luigi M. Biasucci, Dominick 1. Angiolillo and Giovanna Liuzzo

Inflammation as a marker of outcome in myocardial ischemia .............. 221

John Danesh and Rory Collins

Antibiotics in the prevention of coronary heart disease: review of
the randomised trials . . ...... ....... ... .. . ... 237

Tom Saldeen and Jay L. Mehta

Fish oil - a potential therapy for inflammatory atherosclerosis .................. 243

Index .............................................................................. 259

vi
List of contributors

Dominick J. Angiolillo, Institute of Cardiology, Catholic University, Largo Vito,

00168 Roma, Italy

Anupam Agarwal, Division of Nephrology, Hypertension and Transplantation, Box

100224 JHMHC, 1600 SW Archer Road, University of Florida, Gainesville, FL
32610, USA; e-mail: [email protected]

Luigi M. Biasucci, Institute of Cardiology, Catholic University, Largo Vito, 00168

Roma, Italy; e-mail: [email protected]

Allen P. Burke, Department of Cardiovascular Pathology, Armed Forces Institute of

Pathology, 6825 16th Street, N.W., Washington, DC 20306-600, USA

Anton E. Becker, Department of Cardiovascular Pathology, Academic Medical Cen-

ter, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Nether-
lands

Onno J. de Boer, Department of Cardiovascular Pathology, Academic Medical Cen-

ter, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Nether-
lands

Hongjiang Chen, Cardivascular Medicine, Central Arkansas Veteran's Healthcare

System and University of Arkansas for Medical Sciences, 4301 West Markham, Slot
532, Little Rock, AR 72205-7199, USA

Mingyi Chen, National Cardiovascular Center Research Institute, Suita, Osaka

565-8565, Japan; e-mail: [email protected]

Fabrizio Clementi, Department of Cardiology, University of Rome "Tor Vergata",

Rome, Italy
List of contributors

Rory Collins, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield
Department of Clinical Medicine, University of Oxford, Radcliffe Infirmary, Oxford
OX2 6HE, UK

John Danesh, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield
Department of Clinical Medicine, University of Oxford, Radcliffe Infirmary, Oxford
OX2 6HE, UK; e-mail: [email protected]

Helmut Drexler, Abteilung Kardiologie und Angiologie, Medizinische Hochschule

Hannover, Carl Neuberg Strasse 1, Germany;
e-mail: [email protected]

Mark 1. Entman, Department of Medicine, Section of Cardiovascular Sciences, Bay-

lor College of Medicine, One Baylor Plaza, M.S. F-602, Houston, TX 77030, USA;
e-mail: [email protected]

Andrew Farb, Department of Cardiovascular Pathology, Armed Forces Institute of

Pathology, 6825 16th Street, N.W., Washington, DC 20306-600, USA

Nikolaos Frangogiannis, Department of Medicine, Section of Cardiovascular Sci-

ences, Baylor College of Medicine, One Baylor Plaza, M.S. F-602, Houston, TX
77030, USA; e-mail: [email protected]

Nathalie Hill-Kapturczak, Department of Medicine, Box 100224 JHMHC, 1600

SW Archer Road, University of Florida, Gainesville, FL 32610, USA

Shuntaro Kagiyama, Physiology College of Medicine, Box 100274, University of

Florida, Gainesville, FL 32610, USA

Frank D. Kolodgie, Department of Cardiovascular Pathology, Armed Forces Insti-

tute of Pathology, 6825 16th Street, N.W., Washington, DC 20306-600, USA

Giovanna Liuzzo, Institute of Cardiology, Catholic University, Largo Vito, 00168

Roma, Italy

Antonino Mazzone, Unita di Cardiologia, Medicina Generale II, Ospedale Civile di

Legnano, Via Candiani 2, 20025 Legnano (Milan), Italy

David A. Morrow, Cardiovascular Division, Brigham and Women's Hospital, 75

Francis Street, Boston, MA 02115, USA; e-mail: [email protected]

viii
 list of contributors

Harry S. Nick, Department of Neuroscience, University of Florida, Gainesville FL

32610, USA

M. Ian Phillips, Physiology College of Medicine, University of Florida, Gainesville,

FL 32610, USA; e-mail: [email protected]

Paul M. Ridker, Cardiovascular Division, Brigham and Women's Hospital, 75 Fran-

cis Street, Boston, MA 02115, USA; e-mail: [email protected]

Francesco Romeo, Department of Cardiology, University of Rome "Tor Vergata",

Rome, Italy

Tom Saldeen, Department of Surgical Sciences, University of Uppsala, Dag Ham-

marskjolds vag 17, 75237 Uppsala, Sweden; e-mail: [email protected]

Tatsuya Sawamura, National Cardiovascular Center Research Institute, Suita,

Osaka 565-8565, Japan; e-mail: [email protected]

Bernhard Schieffer, Abteilung Kardiologie und Angiologie, Medizinische

Hochschule Hannover, Carl Neuberg Strasse 1,30625 Hannover, Germany;
e-mail: [email protected]

Gerd Schmitz, Institute for Clinical Chemistry and Laboratory Medicine, Universi-
ty of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany;
e-mail: [email protected]

Stefano De Servi, Unit?! di Cardiologia, Ospcdale Civile di Legnano, Via Candiani 2,

20025 Legnano (Milan), Italy; e-mail: [email protected]

Heraldo P. Souza, Molecular and Cellular Biophysics Laboratories, Department of

Medicine, Division of Cardiology and The Electron Paramagnetic Resonance Cen-
ter, The Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Cir-
cle, Baltimore, Maryland 21224, USA; Disciplina de Emergencias Clfnicas, Facul-
dade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil;
e-mail: [email protected]

Michael Torzewski, Institute for Clinical Chemistry and Laboratory Medicine, Uni-
versity of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Ger-
many; e-mail: [email protected]

ix
List of contributors

Allard C. van der Wal, Department of Cardiovascular Pathology, Academic Medical

Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The
Netherlands; e-mail: [email protected]

Renu Virmani, Department of Cardiovascular Pathology, Armed Forces Institute of

Pathology, 6825 16th Street, N.W., Washington, DC 20306-600, USA;
e-mail: [email protected]

Keith A. Youker, Department of Medicine, Section of Cardiovascular Sciences, Bay-

lor College of Medicine, One Baylor Plaza, M.S. F-602, Houston, TX 77030, USA;
e-mail: [email protected]

Dani S. Zander, Department of Pathology, Immunology, and Laboratory Medicine,

University of Florida College of Medicine, Box 100275, Gainesville, FL 32610,
USA; e-mail: [email protected]

Jay L. Zweier, Molecular and Cellular Biophysics Laboratories, Department of

Medicine, Division of Cardiology and The Electron Paramagnetic Resonance Cen-
ter, The Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Cir-
cle, Baltimore, MD 21224, USA; e-mail: [email protected]

x
Preface

There has been a major decline in mortality from atherosclerotic cardiovascular dis-
ease in the last three decades. Much of this decline has come from identification of
so called "risk factors", and better control of smoking, diabetes mellitus, high blood
pressure, and hyperlipidemia. Major strides have been made in developing effective
medical and surgical strategies for primary and secondary prevention of atheroscle-
rosis and related diseases. However, atherosclerosis is still the major cause of mor-
tality in the Western world, and rapidly replacing malnutrition and infectious dis-
ease in the developing world as the cause of morbidity and mortality.
Interestingly, over the last decade there has been a resurgence of interest in
inflammation that accompanies atherosclerosis. Publication of several papers on
this subject in several journals in the last few years would suggest a relatively recent
discovery of this concept. Virchow and Rokitanksy actually made the observation
of inflammation accompanying atherosclerotic vascular disease in the1850s. Cregg
in 1894 and Oster in 1908 commented on the potential infectious etiology of ath-
erosclerosis along with smoking, diabetes, obesity and aging.
The medical and lay literature is emphasizing the role of anti-infectious agents as
potential ground-breaking novel therapy for atherosclerosis. The foundation of this
concept lies in the fact that the decline in cardiovascular mortality over the last half-
century parallels the advent and frequent use of a variety of antibiotics. However, a
similar parallelism can be shown with a number of other treatment modalities.
The late Russell Ross started his last review in the New England Journal of Med-
icine (1999) with a provocative statement: "Atherosclerosis is an inflammatory dis-
ease". I believe the cause and effect relationship between inflammation and athero-
sclerosis is far from proven. Inflammation in atherosclerosis could well be a
response, and a protective one, to arterial injury.
This book attempts to bring together worldwide experts on inflammation in ath-
erosclerosis to present their thoughts in this area. The first four chapters deal with
the theoretical and pathological aspects of inflammation. The next six chapters dis-
cuss the contribution of free radicals, oxidized low-density lipoproteins, and
angiotensin II in inflammation and possibly atherosclerosis. The last four chapters
Preface

are focused on the description of the clinical aspects of inflammation and infection,
and the prognostic value of inflammatory mediators. I invited Drs. Danesh and
Saldeen to present a review of two interesting modes of combating inflammation by
antibiotics and n-3 polyunsaturated fatty acids.
All authors have done a phenomenal job in meeting the challenge. I hope this
volume will be useful to investigators, basic scientists and clinicians alike in further
defining the pathophysiologic role of inflammation in atherosclerosis.

Little Rock, autumn 2000 J.L. Mehta

xii
Atherosclerosis: an inflammatory disease

Gerd Schmitz and Michael Torzewski

Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-

Josef-StrauB-Allee 11, 93053 Regensburg, Germany

Introduction

Cellular processes in atherogenesis with the exception of calcification and throm-

botic events are principally no different to those found in chronic inflammatory-
fibroproliferative diseases such as liver cirrhosis, rheumatoid arthritis, glomeru-
losclerosis, pulmonary fibrosis, or chronic pancreatitis [1]. Atherosclerotic lesions
are the result of a series of highly specific cellular and molecular responses to vari-
ous endogenous risk factors and potential exogenous antigens. These responses are
mediated by endothelial cells, monocyte-derived macrophages, smooth muscle cells
and specific subtypes of T lymphocytes. Activation of these cells leads to the release
of a wide spectrum of inflammatory hydro lases, cytokines, chemokines and growth
factors followed by cellular lipid accumulation and proliferation of smooth muscle
cells as well as formation of fibrous tissue [2]. The modified response-to-injury
hypothesis of atherosclerosis that emphasizes endothelial dysfunction rather than
denudation as the first step in atherosclerosis [1] was recently extended suggesting
that the key initiating event in early atherosclerosis is the subendothelial retention
of cholesterol-rich, atherogenic lipoproteins bound to arterial proteoglycans
(response-to-retention hypothesis) [3]. Following adherence to endothelial cells,
defined subpopulations of circulating monocytes that express the lipopolysaccharide
(LPS) receptor CD14 and the FcyRIIIICD16 (CD14bright CD16+) might extravasate
into the subendothelial space [4-6]. Within the vessel wall phagocytic monocytes
rapidly transform to foam cells characterized by the excessive uptake of atherogenic
lipoproteins by receptor-mediated endocytosis. Cellular uptake of these lipids and
lipoproteins is mediated by charge and motif receptors (scavenger receptors) direct-
ly recognizing non-opsonized ligands. Alternatively, modified lipids and lipoproteins
may be opsonized by either innate (complement components, C-reactive protein
(CRP), serum amyloid P (SAP), serum amyloid A (SAA)) and/or specific opsonins
(immunoglobulins) prior to cellular uptake mediated by different opsonin receptors
including complement receptors, pentraxin family receptors and/or Fey-receptors.
Continuous exposure to modified lipoproteins is supposed to trigger a chronic

Inflammatory and Infectious BasiS of Atherosclerosis, edited by Jay L. Mehta

© 2001 Birkhauser Verlag
IV Cl
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secretion of
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Figure 1
Differentiation of monocytes and blood dendritic cells to either macrophages or antigen-presenting and dendritic cells within the vas-
cular wall. Continuous exposure to modified lipoproteins is supposed to trigger a chronic inflammatory process within the lesion. GM-
CSF, granulocyte-macrophage colony-stimulating facor; IL-4, interleukin 4; M-CSF, macrophage colony-stimulating factor; LDL, low-
density lipoprotein.
 Atherosclerosis: an inflammatory disease

inflammatory process within the lesion. At the monocyte/macrophage level, this

leads to the differentiation of either a phagocytic or an antigen-presenting pheno-
type (Fig. 1) with enhanced expression of procoagulant and proinflammatory genes
as well as genes associated with lipid metabolism [7]. At the smooth muscle cell
(SMC) level, complement activation by CRP [8], SAA or hydrolase-modified low-
density lipoprotein (LDL) [9] takes place even in the early atherosclerotic lesion.
Sublytic complement attack on SMCs leads to the local release of monocyte chemo-
tactic protein 1 (MCP-l), a specific monocyte chemoattractant [10].

Monocyte subpopulations

In normal subjects, five different subpopulations of blood monocytes have been dis-
criminated by cell expression densities of various antigens involved in extravasation,
uptake of atherogenic lipoproteins, differentiation and inflammation. The Fcy recep-
tors, in particular CDI6alFcyRIII, together with the LPS receptor CDI4, appear to
be key players in defining monocyte subpopulations. Their heterogeneous expression
suggested a different capacity for IgG-dependent phagocytosis [4]. The pool size of
CDI4dim CDI6+ monocytes correlates with plasma lipids and lipoprotein metabolism
as well as inflammation and the acute phase reaction (Fig. 2) stressing a link between
peripheral blood monocyte heterogeneity and cardiovascular risk factors.

Chemically-modified lipids and lipoproteins as endogenous antigens

The transformation of macrophages to foam cells in situ has been widely accepted
as being derived from the cellular uptake of different forms of chemically-modified
lipids and lipoproteins (Tab. 1). Oxidation of lipoproteins is one such modification
likely occurring in lesions in vivo and promoting certain atherogenic processes [11].
Major questions remain, however, concerning the oxidation hypothesis, in particu-
lar in terms of particle morphology, macrophage foam cell formation, and comple-
ment activation. Thus, there has been increasing interest in other modifications of
lipoproteins that may be important in atherogenesis. These include AGE-LDL
(advanced glycosylation end-products), LDL-heparan sulfate-like and dermatan sul-
fate proteoglycan complexes, LDL modified by PLA2 (phospholipase A2l and aggre-
gated LDL [12]. In patients with diabetes, increased levels of LDL modified by
AGEs have been found in the plasma as well as in atherosclerotic lesions [13]. LDL-
proteoglycan complexes are internalized by cultured macrophages and smooth mus-
cle cells leading to foam cell formation [14]. Uptake of LDL-proteoglycan com-
plexes in human monocyte-derived macrophages is not mediated through binding to
the LDL receptor, but occurs predominantly via class A scavenger receptors [15].
Recently, it was demonstrated that the secretory group II phospholipase A2 expres-

3
Gerd Schmitz and Michael Torzewski

w 10'
c..

o
'<t

.
"'-
U
.....
:I: :
~ ~'"
LL
10<
FL1 - H/CD16 FITC - - - - - - - - - - --

Phenotype of C014dim C016+ peripheral blood monocytes (MNP 3) correlates

Positively to Negatively to Ref.

Plasma lipids and lipoproteins HDL -cholesterol [4]

plasma cholesterol and
triglycerides [6]
apoE4 allele [5]

Inflammation, acute phase reaction M-CSF therapy [81]

GM-CSF therapy [82]
tuberculosis [83]
solid tumors [84]
sepsis [85]
HIV infection [86, 87]

Figure 2
Correlation of the pool size of C014 dim C016+ monocytes (MNP 3) to plasma lipids and
lipoprotein metabolism as well as inflammation and the acute phase reaction. Subpopula-
tions of mononuclear phagocytes (MNP 1-5) were discriminated by flow-cytometry (top)
due to their expression pattern of C016 and C014. M-CSF, macrophage colony-stimulating
factor; GM-CSF, granUlocyte-macrophage colony-stimulating facor

4
 Atherosclerosis: an inflammatory disease

Table 1 - Atherogenic lipids and lipoproteins

Lipids/Lipoproteins Atherogenic molecular component Refs.

oxidized LDL (ox-LDL) hydroperoxy- and hydroxy fatty acids, [11, 88, 89]
secondary aldehydic lipid peroxidation
products, 7 ~-hydroperoxycholesterol
acetylated LDL (ac-LDL) acetylated lipids [90]
enzymatically degraded LDL (E-LDL) free cholesterol, Iysophospholipids [20]
LDL -proteoglycan complexes basic amino acid residues 3359-3369 [91]
in site B of apo-B1 00
lipoproteins aggregated by PLA2 , PLC Iysophosphatidylcholine, phosphatidic [19,21]
acid, lysophosphatidic acid
LDL hydrolyzed by sphingomyelinase ceramide, phosphocholine [92]
LDL hydrolyzed by phospholipase C Iysophosphatidylcholine, phosphatidic [18]
acid, lysophosphatidic acid
LDL modified by advanced glycation 67 amino acid domain located 1791 [93]
end products (AGEs) residues N-terminal to the LDL receptor
binding site of apo-B
modification of residues adjacent to the [94]
putative LDL receptor binding site
gangliosides (sialic acid containig sialic acid [95]
glycosphingolipids)

sion in human aortic tissue correlates with the degree of atherosclerosis [16]. Final-
ly, many in vitro treatments of LDL, such as vortexing or extensive hydrolysis by
both phospholipase A2 [17] and phospholipase C [18] lead to aggregation. Aggre-
gated lipoproteins are prominent in atherosclerotic lesions [19]. Cellular uptake of
these modified lipids and lipoproteins is mediated by various members of the scav-
enger receptor family and the receptor for AGE (RAGE) [13]. These receptors are
charge and motif receptors directly recognizing non-opsonized ligands.
Analogous to well known concepts of host defence in infectious diseases, non-
oxidative, partial hydrolysis of lipids and lipoproteins by the hydrolytic host defence
machinery transforms lipoproteins to an atherogenic moiety. Treatment of LDL
with degrading enzymes in vitro converts the molecule to a complement-activating
moiety (see below), which is rapidly taken up by human macrophages and thus
inducing foam cell formation [20]. In correlation to these in vitro findings, lipopro-
tein particles resembling large droplet structures (10-200 nm in diameter) formed
during enzymatic degradation of LDL (E-LDL) have been visualized in, and extract-
ed from, atherosclerotic lesions [9, 21]. Moreover, E-LDL has been detected by

5
Gerd Schmitz and Michael Torzewski

immunohistochemistry using specific monoclonal antibodies in early atherosclerot-

ic lesions of human coronary arteries [22].

Potential opsonins for modified LDL and their receptors

Modified lipids and lipoproteins like E-LDL might be recognized via opsonin-medi-
ated processes by either innate (complement components, CRP, SAP, SAA) and/or
specific opsonins (immunoglobulins) prior to cellular uptake via opsonin receptors.
C-reactive protein (CRP) has recently been classified as innate recognition lectin
[23]. During the last five years, the predictive association between CRP and coro-
nary heart disease (CHD) has been extensively confirmed [24, 25]. Furthermore,
CRP is emerging as a key modulator of inflammatory processes in early atherogen-
esis, in particular due to its known complement activating [26], lipoprotein-binding
[27] and chemotactic [28] properties. Of particular importance might be calcium-
dependent in vitro binding of CRP to E-LDL accompanied by an enhancement of
complement activation [29]. Different receptors have been described for CRP. On
monocytes, specific CRP binding occurs through FcyRIICD64 [30] as well as
FcyRIIICD32 [31]. However, there might be an additional "unique" CRP-receptor
involved in CRP signalling [32]. At this stage additional research is needed to clari-
fy the contribution of the different receptors to CRP binding [33].
Serum amyloid P (SAP) is the second pentraxin present in human plasma, which
also has been reported to locate to atherosclerotic lesions and bind to a variety of
ligands such as C4b-binding protein, CRP, complement components Clq and C3bi,
and human IgG in a calcium-dependent manner. SAP specifically interacts with
high-density lipoproteins as well as very low-density lipoproteins but not with low-
density lipoproteins [34] and can activate the complement system [35]. The presence
of glycoprotein receptors for mouse SAP on elicited, inflammatory macrophages
suggests that cellular uptake of SAP might occur via specific receptors [36].
Serum amyloid A (SAA), a family of acute-phase reactants, is found on high-den-
sity lipoproteins (HDL) and displaces apolipoprotein AI from HDL particles and
converts a-migrating mature HDL back to pre~rprecursor HDL particles [37]. Fur-
ther functions for the SAAs include participation in detoxification, depression of
immune responses, and interference with platelet functions [38]. In human athero-
sclerotic lesions, SAA mRNA was found in most endothelial cells and some smooth
muscle cells as well as macrophage-derived foam cells, adventitial macrophages, and
adipocytes [39]. Formyl peptide receptor-like 1 (FPRLl), a member of the G-pro-
tein-coupled receptor family with low affinity for N-formylmethionyl-1-leucyl-1-
phenylalanine (fMLP), mediates the chemotactic activity of SAA in human phago-
cytic cells [40].
Differential screening of a cDNA library constructed from human umbilical vein
endothelial cells exposed to interleukin-1~ (IL-l~) has led to the identification of

6
 Atherosclerosis: an inflammatory disease

PTX3, a novel pentraxin gene. PTX3 is expressed and released from cells of the
monocyte-macrophage lineage exposed to inflammatory signals and thus may rep-
resent an additional marker of inflammatory reactions, particularly those involving
the vessel wall [41].
Antibodies, as specific opsonins against different epitopes of lipids and lipopro-
teins (charge modified phospholipids, cholesterol or cryptic protein epitopes), have
been demonstrated in human plasma. Injection of silicone gel or silicone oil
intraperitoneally into BALB/c mice induced the formation of antibodies that react-
ed with highly purified crystalline cholesterol and, to a much lesser extent, with
phospholipids [42]. Human IgG1 and IgG3 autoantibodies reactive with ox-LDL
have been isolated from human plasma [43]. Experimental studies demonstrated the
involvement of FcyRIICD64 in cellular uptake of LDL-immune complexes [44] and
metabolism of LDL aggregates [45]. In addition, it was shown that cholesterol
depletion leads to down-regulation of FcyRIICD64 on the human monocyte-like cell
line U937 [46]. The involvement of FcyRIIICD32 in cellular uptake of LDL-immune
complexes is a subject being lively debated [47,48].
Taken together, modified lipids and lipoproteins opsonized by innate andlor spe-
cific opsonins might facilitate foam cell formation (Fig. 3).

Chronic inflammatory processes

Continuous exposure to modified lipoproteins is supposed to trigger a chronic

inflammatory process within the lesion. At the monocyte/macrophage level this
leads to the differentiation of either a phagocytic or an antigen-presenting pheno-
type with expression of procoagulant and pro inflammatory genes as well as genes
associated with lipid metabolism [7]. Various pathways might be responsible. The
~2 integrin CR3 (CDllb/CD18) is required for tyrosine phosphorylation initiating
the focal adhesion kinase (FAK)/paxillin signal transduction pathways [49]. CRP
binding to the CRP-R has been demonstrated to alter IL-8-induced signalling in neu-
trophils [50]. Fey receptors are associated with the immunoreceptor tyrosine-based
activation motif (ITAM), that modulates activation of tyrosine kinases of the Src
and ZAP-70 families. Subsequent events, which vary depending on the cell type and
receptors involved, include activation of other enzymes such as phospholipase C,
phospholipase D, phosphatidylinositol-3-kinase, and mitogen-activated protein
kinase [51,52].

Exogenous antigens in atherogenesis

Analogous to modified lipoproteins as endogenous antigens, suggested antigenic

stimuli involved in the pathogenesis and progression of atherosclerosis also include