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Pathogenesis ofPathogenesis of
AtherosclerosisAtherosclerosis
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Various immunodeficiencies
Hyperinflammatory but inadequate
immune response
Clinical picture of (Hemophagocyticlymphohistiocytosis) HLH
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HLHVariable course of disease
Rapidly progressive leading to death within
weeks
Transient improvements with unspecifictherapies
Disappearance of symptoms without therapy
Disappearance of symptoms with immuno-suppressive/immunomodulatory drugs
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HLHClassification
Genetic, primary HLH Acquired, secondary HLHFHLH
- Perforin mutations (chr.10) Exogenous agents
- infectious organisms, toxins- Chromosom 9 linkage (VAHS, IAHS)
- Unknown mutations HLH Endogenous products- tissue damage
- radical stress
- Immune deficiencies - metabolic productsCHSGriscelli syndrome Rheumatic disorders
XLP Malignancies
SCID
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HLH
Diagnostic criteria Histiocyte Society 1991
Clinical
Fever > 38.5
Splenomegaly
LaboratoryCytopenia of => 2/3 cell lines
Hypertriglyceridemia and/or
hypofibrinogenemiaHistopathology
Hemophagocytosis in bone marrow
or spleen or liver or lymphnode
Strong supportive evidence are spinal fluid pleocytosis, liver
histology resembling chronic persistent hepatitis, low natural
killer cell activity
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HLH
Therapy
Cytostatic and immunsuppressive/
immunomodulatory drugs:
Corticosteroids, Cyclosporin A,Etoposide
Immunoglobulins, Antithymocyte globulin
h Bone marrow transplantation
Prognosis
In 20% no response to therapy
After BMT 60-70% relapse-free survival
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IntroductionIntroduction
ArteriosclerosisArteriosclerosis Thickening and loss of elasticity of arterialThickening and loss of elasticity of arterial
wallswalls
Hardening of the arteriesHardening of the arteries
Greatest morbidity and mortality of allGreatest morbidity and mortality of all
human diseases viahuman diseases viaNarrowingNarrowing
WeakeningWeakening
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Atherosclerotic DiseaseAtherosclerotic Disease
PrevalencePrevalence In US there are 6 million with CADIn US there are 6 million with CAD
3 million Americans have had strokes3 million Americans have had strokes
MortalityMortality
1.5 million deaths/yr in US due to1.5 million deaths/yr in US due to
myocardial infarctionmyocardial infarction 0.5 million deaths/yr in US due to strokes0.5 million deaths/yr in US due to strokes
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Three patterns of arteriosclerosis
Atherosclerosis Thedominant pattern of arteriosclerosis
Primarily affects the elastic (aorta, carotid,
iliac) and large to medium sized muscular
arteries (coronary, popliteal)
Monckeberg medial calcific sclerosis Arteriolosclerosissmall arteries and
arterioles (hypertension and DM)
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NonNon--Modifiable Risk FactorsModifiable Risk Factors
AgeAge A dominant influenceA dominant influence
Atherosclerosis begins in the young, but does notAtherosclerosis begins in the young, but does notprecipitate organ injury until later in lifeprecipitate organ injury until later in life
GenderGender Men more prone than women, but by age 60Men more prone than women, but by age 60--7070
about equal frequencyabout equal frequency
Family HistoryFamily History Familial cluster of risk factorsFamilial cluster of risk factors
Genetic differencesGenetic differences
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Modifiable Risk FactorsModifiable Risk Factors
(potentially controllable)(potentially controllable)
HyperlipidemiaHyperlipidemia
HypertensionHypertension
Cigarette smokingCigarette smoking
Diabetes MellitusDiabetes Mellitus Elevated HomocysteineElevated Homocysteine
Factors that affect hemostasis andFactors that affect hemostasis andthrombosisthrombosis
Infections: Herpes virus; ChlamydiaInfections: Herpes virus; Chlamydiapneumoniaepneumoniae
Obesity, sedentary lifestyle, stressObesity, sedentary lifestyle, stress
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Fig. 11.7
AHA Classification of atherosclerosis
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Normal Artery
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Normal Artery
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AtherosclerosisAtherosclerosis
A disease of the intimaA disease of the intima
A disease of the intimaA disease of the intima A disease of the intimaA disease of the intima
AtheromasAtheromas,, atheromatous/fibrofattyatheromatous/fibrofatty
plaques, fibrous plaquesplaques, fibrous plaques Narrowing/occlusion; weakness of wallNarrowing/occlusion; weakness of wall
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Major components of plaque
Cells (SMC, macrophages and other WBC)
ECM (collagen, elastin, and PGs)
Lipid = Cholesterol (Intra/extracellular)
(Often calcification)
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Two major processes in plaque
formation
Intimal thickening (SMC proliferation and
ECM synthesis)
Lipid accumulation
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Consequences of plaque
formation
Generalized
Narrowing/Occlusion
Rupture
Emboli
Leading to specific problems: Myocardial and cerebral infarcts
Aortic aneurysms
Peripheral vascular disease
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Fatty Streak-Aorta
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Fatty Streak-Coronary Artery
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Altered Vessel Function
Consequence
Ischemia, turbulence
Aneurysms, vessel
rupture Narrowing, ischemia,
embolization
Athero-embolization
Increase systolic blood
pressure
Vessel change Plaque narrows
lumen
Wall weakened
Thrombosis
Breaking loose ofplaque
Loss of elasticity
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Late Changes
Calcification
An example of dystrophic calcification
Cracking, ulceration, rupture Usually occurs at edge of plaque
Thrombus formation
Caused by endothelial injury,ulceration, turbulence Organization of thrombus
More thrombus
Encroachment Weakens vessel wall
Bleeding
Ulceration, cracking and angiogenesis
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ATHEROSCLEROSIS:
Pathology, Pathogenesis, Complications, Natural History
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Complicated LesionsFibrous Plaques
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Neovas.Calcification
Inflam. cells
Fibrous cap
Cholesterol clefts
Elastin membrane
destroyed
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Hemorrhage into Plaque
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Ulceration/Hemorrhage/Cholesterol Crystals
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Complicated Lesion/Calcification
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Cholesterol Crystals/Foam Cells
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Thrombosis/Complicated Lesion
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Complicated Lesion/Ulceration/Thrombosis
A ti A
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Aortic Aneurysm
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Aortic Aneurysm
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Pathogenesis of Atherosclerosis
Cause? Current hypothesis: Response to Injury
Initiated by endothelial dysfunction
Disease of the intima
Intimal thickening
Intra- and extra-cellular lipid accumulation Chronic Inflammation
Basic Lesion: is termed atheroma, fibro-fatty
plaque, or atheromatous plaque
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Response to injury hypothesis
* Injury to the endothelium
(dysfunctional endothelium)
* Chronic inflammatory response
* Migration of SMC from media to intima
* Proliferation of SMC in intima
Excess production of ECM Enhanced lipid accumulation
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Response to injury hypothesis (I)
1. Chronic EC injury (subtle?)
EC dysfunction
Increased permeability
Leukocyte adhesion (via VCAM-1)
Thrombotic potential
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Response to injury hypothesis (II)
2. Accumulation of LDL (cholesterol)
3. Oxidation of lesional LDL
4. Adhesion & migration of blood
monocytes; transformation intomacrophages and foam cells
5. Adhesion of platelets6. Release of factors from platelets,
macrophages and ECs
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Response to injury hypothesis (III)
7. Migration of SMC from media to intima
8. Proliferation of SMC
9. ECM production by SMC
10. Enhanced lipid accumulation
Intracellular (SMC and macrophages)
Extracellular
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Endothelial dysfunction
Induced by oxidized LDL, can be worsened by
cigarette smoking, and can be reversed with
correction of hyperlipidemia by diet or by therapy
with a statin, which increases the bioavailability of
nitric oxide, with ACE inhibitors, or with
antioxidants such as vitamin C or flavonoids
contained in red wine Anderson et al., 1996; Harison et al 1987; John et al., 1998; Mancini et al 1996; Levineet al 1996
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Endothelial dysfunction
Expression of VCAM-1 on endothelial
surfaces is an early, and necessary, step in
the pathogenesis of atherosclerosis.
Increased cellular adhesion and associatedendothelial dysfunction then sets the stage
for the recruitment of inflammatory cells,release of cytokines and recruitment of lipid
into the atherosclerotic plaque.Li et al., 1993
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Dyslipidaemia
Lipid abnormalities play a critical role in
the development of atherosclerosis
Early experiments demonstrated accelerated
atherosclerosis with a high cholesterol diet.
Epidemiologic studies showed increasing
incidence of atherosclerosis when serumcholesterol above 3.9 mM
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Dyslipidaemia High levels of LDL and low levels of HDL
important risk factors for atherosclerosis Macrophage uptake of LDL may initially be
adaptive response, which prevents LDL-induced
endothelial injury
However, cholesterol accumulation in foam cellsleads to mitochondrial dysfunction, apoptosis, andnecrosis, with resultant release of cellular
proteases, inflammatory cytokines, andprothrombotic molecules
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Dyslipidaemia
Oxidized LDL can cause disruption of the
endothelial cell surface, promote
inflammatory and immune changes via
cytokine release from macrophages andantibody production and increase platelet
aggregation
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Dyslipidaemia
HDL, in contrast to LDL, has
antiatherogenic properties that include
reverse cholesterol transport, maintenance
of endothelial function, protection againstthrombosis, and maintenance of low blood
viscosity through a permissive action on red
cell deformability
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Inflammation
Best evidence supporting the importance of
inflammation in the pathogenesis of
atherosclerosis comes from the observation
that markers of increased or decreasedsystemic inflammation are directly
associated with the risk of atherosclerosis
Inflammation and chronic
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Inflammation and chronic
endothelial injury
VCAM-1 expression increases recruitment of
monocytes and T-cells to sites of endothelial
injury
Subsequent release of MCP-1 by leukocytesmagnifies the inflammatory cascade by recruiting
additional leukocytes, activating leukocytes in the
media, and causing recruitment and proliferationof smooth muscle cells
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Atherosclerosis is initiated when
leucocytes adhere to the
endothelium as a result ofexpression of adhesive proteins.
Crowther et al., 2005
Inflammation and chronic
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Inflammation and chronic
endothelial injury
Monocytes adhere to the endothelium and
then migrate through the endothelium and
basement membrane by elaborating
enzymes, including locally activated matrixmetaloproteinases (MMP) that degrade the
connective tissue matrix
Crowther et al., 2005
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Leucocytes than cross the
endothelial barrier and begin to
accumulate
Crowther et al., 2005
Inflammation and chronic
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Inflammation and chronic
endothelial injury
Macrophages both release additional cytokines
and begin to migrate through the endothelial
surface into media of the vessel.
This process is further enhanced by the localrelease of M-CSF, which causes monocytic
proliferation
Local activation of monocytes leads to bothcytokine-mediated progression of atherosclerosis,
and oxidation of LDL
Crowther et al., 2005
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Monocytes within the sub-
endothelial space subsequentlyorchestrate the development of
atherosclerosis through cytokine
release.
Crowther et al., 2005
Inflammation and chronic
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Inflammation and chronic
endothelial injury
CD40L elaborated within the plaque has
been shown to increase the expression of
tissue factor in atherosclerotic plaques
anti-CD40L abrogates evolution ofestablished atherosclerotic lesions in animal
models
Schonbeck et al., 2000
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Clinically apparent disease if first
noted as a result of the
accumulation of foam cells.
Crowther et al., 2005
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Inflammatory mediators
Include IL-1, TNF and , IL-6, M-CSF,
MCP-1, IL-18 and CD-40L.
The impact of these mediators is diverse
and includes mitogenesis, intracellularmatrix proliferation, angiogenesis and foam
cell development
Crowther et al., 2005
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The clinically important lesion is characterized by
intimal narrowing, many foam cells,
neovascularization and flow limiting narrowing.
However, this stage of the disease is sufficiently
advanced that treatments aimed at it do not
impact the pathogenesis of the underlying disorder.
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CRP CRP may be only a marker of inflammation and
thrombotic risk CRP binds to LDL, allowing LDL to be taken up
by macrophages without the need for modification
CRP induces adhesion molecule expression andproduction of IL-6 and MCP-1 in humanendothelial cells; these effects might enhance a
local inflammatory response within theatherosclerotic plaque by the recruitment ofmonocytes and lymphocytes
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CRP The proinflammatory and prothrombotic effects of
CRP on monocytes and endothelial cells in vivoby subjecting wild-type mice, which do not
express CRP, and human CRP-transgenic (CRPtg)
mice to two models of arterial injury.
In an arterial injury model complete thrombotic
occlusion of the femoral artery at 28 days wasseen in 17% of wild-type mice compared with
75% of CRPtg arteries.
Danenberg et al., 2003
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Multivariable-adjusted relative risks of
cardiovascular disease according to levels of CRP
and the estimated 10-year risk based on theFramingham Risk Score. CHD indicates coronary
heart disease. Data from Ridker and colleagues
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IL-1 and TNF-alpha Enhance expression of cell surface
molecules such as ICAM-1, VCAM-1,
CD40, CD40L, and selectins on endothelial
cells, smooth muscle cells, & macrophages Induce cell proliferation, contribute to the
production of ROS, stimulate matrixmetalloproteinases, & induce TF expression
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Leukocyte activation mRNA profiles showing increased levels of
most inflammatory mRNAs in individuals
with prior AMI
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Toll-like receptor 4 Polymorphisms in the toll-like receptor 4 gene that
confer differences in the inflammatory response toGram negative pathogens
Carriers of the Asp299Gly polymorphism,compared to wild-type alleles, have reduced
circulating levels of inflammatory markers,
including CRP, adhesion molecules, and IL-6, anda reduced incidence of carotid atherosclerosis
Molecular Targets to address chronic
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g
inflammation
Peroxisome proliferator-activated receptors
(PPARs) have emerged as important anti-atherogeneic targets
Endothelial specific roles of PPAR- include inhibition of adhesion molecules, including VCAM-1
increased endothelial NO release
reduced foam cell formation reduced uptake of glycated LDL and triglyceride-rich
remnant lipoproteins
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PPARs Ligands of PPAR- include fatty acids and
the oral hypoglycemic drugs belonging to
the glitazone family
PPAR- is expressed in numerous cell typesfound within the atherosclerotic lesion,
including endothelial cells, smooth muscle-cells, macrophages, and T cells
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Potential anti-atherogenic activities of peroxisomeproliferator-activated receptors (PPARs)
1. Increased nitric oxide synthesis and release2. Decreased recruitment of T cells
3. Reduced angiogenesis
4. Inhibition of smooth muscle cell (SMC) migration
5. Decreased SMC expression of matrix-degrading enzymes
6. Decreased macrophage-dependent expression of matrix
metalloproteinase (MMP)-9 and osteopontin
7. Enhanced release of the interleukin-1 receptor antagonist8. Enhanced reverse cholesterol transport
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Lucas et al., 2006
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Angiogenesis Angiogenic signaling and proliferation of
microvessels within the plaque is only now
beginning to be understood
Plaque hemorrhage is likely attributable tobleeding from fragile microvessels that
proliferate within the plaque itself,presumably in response to local angiogenic
stimuli.
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Angiogenesis Kockx et al identified intraplaque hemorrhage
from microvessels triggering macrophageactivation and foam cell formation in carotid
lesions
These authors propose that intraplaque
microhemorrhage may initiate platelet and
erythrocyte deposition, lead to iron deposition,activate macrophages and contribute to foam cell
formation.
Kockx et al.,2003
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Angiogenesis The importance of angiogenesis in the
pathogenesis of plaque growth was recentlybolstered by the finding that intra-plaquemicrovessels were an independent predictor of
plaque rupture
The potential importance of angiogenesis in thedevelopment of atherosclerosis is found inexperiments that demonstrate that antiangiogenic
therapy reduced atherosclerotic lesiondevelopment in a placebo controlled trial inatherosclerosis prone mice
Moreno et al., 2004; Chew
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Moreno et al., 2006
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General features of insulin signal transduction pathways.
PI 3-kinase branch of insulin signaling regulates GLUT4
translocation and glucose uptake in skeletal muscle and NO
production and vasodilation in vascular endothelium. MAPkinase
branch of insulin signaling generally regulates growth and
mitogenesis and controls secretion of ET-1 in vascularEndothelium Kim et al., 2006
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Kim et al., 2006
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Shared and interacting mechanisms of
glucotoxicity, lipotoxicity, and inflammation underlie
reciprocal relationships between insulin resistanceand endothelial dysfunction that contribute
to linkage between metabolic and cardiovascular
diseases. CAD indicates coronary artery disease
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Mechanisms for the contribution of
insulin resistance to atherosclerosis.
VSMC indicates vascular smoothmuscle cell; CHF, congestive heart
failure.
Kim et al., 2006
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Tissue factor: A key regulator of coagulation. Tissue factor (TF) is a key
initiator of the coagulation cascade. Formation of a complex with factor VIIa
(FVIIa) leads to activation of factor IX (FIX) and factor X (FX), resulting in
thrombin generation and, ultimately, clot formation. Tissue factor pathway inhibitor
(TFPI), the endogenous inhibitor of TF activity, is synthesized and secreted mainly by
endothelial cells. TFPI binds to FXa and thereby inhibits TF/FVIIa activity.
Steffel et al; 2006
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Induction of tissue factor expression and activity. Induction of tissue factor (TF) is
exemplified in an endothelial cell. Various mediators induce TF expression through
activation of their receptors. Induction of TF primarily occurs at the transcriptional
level, resulting in an increase in TF mRNA and, eventually, TF protein expression. TF
is distributed in three cellular pools as cytoplasmatic TF, surface TF, and encrypted TF.
Moreover, TF-containing microparticles are released from the cell. Alternative splicing
results in a soluble secreted form of TF (asTF). IL-1 indicates interleukin-1; LPS,
lipopolysaccharide; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth
factor; HB1B, histamine HB1B-receptor; 5-HTB2aB, 5-hydroxytryptamineB2aB
receptor; IL1-R, interleukin-1 receptor; TLR-4, toll-like receptor 4; PAR, protease-
activated rece tor; KDR, VEGF rece tor-2. Steffel et al 2006
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Tissue factor in the atherosclerotic plaque. In the inflammatory environment of atherosclerotic
plaques, tissue factor (TF) is present at high levels in endothelial cells, vascular smooth muscle
cells, macrophages/foam cells, and in the necrotic core. TF induction is exemplified by selected
mediators in endothelial cells (EC, left panel), macrophages (M, middle panel), and vascular
smooth muscle cells (VSMC, right panel). On plaque rupture, highly procoagulant material
including TF-containing microparticles is released into the blood, leading to rapid initiation of
coagulation, platelet aggregation, and, ultimately, thrombus formation with vessel occlusion.
Steffel et al; 2006
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Therapeutic approaches. Several therapeutic strategies have been developed to specifically interfere with
the action of tissue factor (TF). Molecular approaches such as ribozymes or antisense oligonucleotidesspecifically inhibit TF production. Monoclonal or polyclonal anti-TF antibodies directly target and inactivate
the TF protein. Site-inactivated factor VIIa (FVIIai) binds to TF but lacks catalytic activity for conversion of
factor X (FX) or factor IX (FIX). Recombinant tissue factor pathway inhibitor (rTFPI) interferes with the
activity of the TF/FVIIa complex by binding to the active site of factor Xa (FXa), leading to formation of a
quaternary inhibitory complex with TF/FVIIa. Similarly, recombinant nematode anticoagulant protein c2(rNAPc2) interferes with the TF/FVIIa complex by binding to FXa or FX before formation of a quarternary
inhibitory complex with TF/FVIIa. Steffel et al 2006
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Response to Injury
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Endothelial Dysfunction
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Initiation of Fatty Streak
Fatty Streak
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ib f A h
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Fibro-fatty Atheroma
Summary of Atherosclerotic ProcessSummary of Atherosclerotic Process
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Multifactorial process (risk factors)Multifactorial process (risk factors)
Initiated by endothelial dysfunctionInitiated by endothelial dysfunction
Up regulation of endothelial and leukocyte adhesionUp regulation of endothelial and leukocyte adhesionmoleculesmolecules
Macrophage diapedesisMacrophage diapedesis
LDL transcytosisLDL transcytosis LDL oxidationLDL oxidation
Foam cellsFoam cells
Recruitment and proliferation of smooth muscle cellsRecruitment and proliferation of smooth muscle cells(synthesis of connective tissue proteins)(synthesis of connective tissue proteins)
Formation and organization of arterial thrombiFormation and organization of arterial thrombi
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Is AtherosclerosisIs Atherosclerosis
R iblR ibl
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ReversibleReversible Primate experimentsPrimate experiments High fat diet discontinued; atherosclerotic lesionsHigh fat diet discontinued; atherosclerotic lesions
regressregress HumansHumans
Decrease fat and caloric intake (wars, famine,Decrease fat and caloric intake (wars, famine,
wasting disease), atheromas decrease.wasting disease), atheromas decrease. Angiography after cholesterol lowering, plaqueAngiography after cholesterol lowering, plaque
size decreasessize decreases
What has to happen for plaques to regress?What has to happen for plaques to regress? LDL loweredLDL lowered
Mac ingest lipidsMac ingest lipids
Reverse cholesterol transport, depends on HDLReverse cholesterol transport, depends on HDL