atherosclerosis. atheroma are not merely filled with lipid, but contain cells whose functions...
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Atherosclerosis Atherosclerosis
Atheroma are not merely filled with lipid, Atheroma are not merely filled with lipid, but contain cells whose functions critically but contain cells whose functions critically influence atherogenesis:influence atherogenesis:
Intrinsic Vascular Wall Cells:
Endothelium
Smooth Muscle Cells
Inflammatory Cells:
Macrophages
T Lymphocytes
Mast Cells
Cell Types in the Human AtheromaCell Types in the Human Atheroma
Monocyte/Monocyte/MacrophageMacrophage
T-lymphocytesT-lymphocytesTunicaMedia
Intima
Smooth musclecells
EndotheliumEndothelium
No No symptomssymptoms ++ Symptoms Symptoms
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Time (y)Time (y)
SymptomsSymptoms
Lesion initiationLesion initiation
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
AttachmentAttachment
Leukocyte–Endothelial Adhesion MoleculesLeukocyte–Endothelial Adhesion Molecules
MonoMonoTT
BB PMNPMN
Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM-1)(VCAM-1)
Binds monocytes and lymphocytes- Cells found in atheroma
Expressed by endothelium over nascent fatty streaks
Expressed by microvessels of the mature atheroma
An atherogenic diet rapidly induces An atherogenic diet rapidly induces
VCAM-1, a cytokine-regulatable VCAM-1, a cytokine-regulatable
mononuclear leukocyte adhesion mononuclear leukocyte adhesion
molecule, in rabbit aortic endotheliummolecule, in rabbit aortic endothelium
Li H et al. Arterioscler Thromb 1993;13:197-204.
VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta
Li H et al. Arterioscler Thromb 1993;13:197-204.
3 weeks on atherogenic diet
PenetrationPenetration
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1(MCP-1)(MCP-1)
A potent mononuclear cell chemoattractant
Produced by endothelial and smooth muscle cells
Localizes in human and experimental atheroma
Absence of monocyte chemoattractant Absence of monocyte chemoattractant
protein-1 reduces atherosclerosis in protein-1 reduces atherosclerosis in
low-density lipoprotein receptor–low-density lipoprotein receptor–
deficient micedeficient mice
Gu L et al. Mol Cell 1998;2:275-281.
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
Gu L et al. Mol Cell 1998;2:275-281.
LDL-R –/–LDL-R –/–
MCP-1 +/+MCP-1 +/+
LDL-R –/–LDL-R –/–
MCP-1 –/–MCP-1 –/–
Gu L et al. Mol Cell 1998;2:275-281.
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
0
5
10
15
20
25
30
Oil
Red S
tain
ing
% A
ort
ic S
urf
ace
Sta
ined
Time on Diet: 12 – 14 weeks
+/+ -/-
***
+/+ -/-
20 – 25 weeks *P = 0.001 compared to +/+**p = 0.005 compared to +/+
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Activation
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Division
Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor (M-CSF)(M-CSF)
A potent monocyte activator and co-mitogen
Produced by endothelial and smooth muscle cells
Localizes in human and experimental atheroma
Augmented M-CSF gene expression in Augmented M-CSF gene expression in
human and experimental atherogenesishuman and experimental atherogenesis
Rosenfeld ME et al. Am J Pathol 1992;140:291-300.Clinton SK et al. Am J Pathol 1992;140:301-316.
M-CSF Expression in AtheromaM-CSF Expression in Atheroma
IntimalM-CSF
inAtheroma
M-CSF Promotes AtherogenesisM-CSF Promotes Atherogenesis
Smith JD et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995;92:8264-8268.
Qiao JH et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997;150:1687-1699.
Rajavashisth T et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest 1998;101:2702-2710.
M-CSF Deficiency (M-CSF Deficiency (opop mutation) Reduces mutation) Reduces Atheroma in LDL Receptor–Knockout MiceAtheroma in LDL Receptor–Knockout Mice
Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.
+/++/+ op/+op/+ op/opop/op
M-CSF Gene Dosage Relates to Atheroma M-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– MiceSize in LDLR –/– Mice
Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.
107
Fatt
y L
esi
ons
in A
ort
ic R
oot
(m
2/s
ect
ion) 106
105
104
103
(10)* (4)
*
(12)
Genotypeop/++/+ op/op
Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis
M-CSFMCP-1
VCAM-1
Anatomy of the Atherosclerotic PlaqueAnatomy of the Atherosclerotic Plaque
LumenLipidCore
Fibrous cap
Shoulder
Intima
MediaElasticlaminæ
Internal
External
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Transition from chronic to acute atheromaTransition from chronic to acute atheroma
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
Thrombosis of a Disrupted Atheroma, the Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Cause of Most Acute Coronary Syndromes, Results from:Syndromes, Results from:
Weakening of Weakening of the fibrous capthe fibrous cap
Thrombogenicity of the lipid core
Illustration courtesy of Michael J. Davies, M.D.
Matrix Metabolism and Integrity of the Matrix Metabolism and Integrity of the Plaque’s Fibrous CapPlaque’s Fibrous Cap
Libby P. Circulation 1995;91:2844-2850.
+ + + +
++
–
Synthesis Breakdown
Lipid core
IL-1TNF-MCP-1M-CSF
FibrouscapIFN-IFN-
CD-40L
Collagen-degradingCollagen-degradingProteinasesProteinases
Tissue FactorTissue FactorProcoagulantProcoagulant
Increased Expression of Interstitial Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M(SMC) and Macrophages (M) in Human ) in Human AtheromaAtheroma
Galis ZS et al. J Clin Invest 1994;94:2493-2503.
Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis
Thrombus Fibrous cap
1 mmLipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Thrombosis of a Disrupted Atheroma, the Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Cause of Most Acute Coronary Syndromes, Results from:Syndromes, Results from:
Weakening of the fibrous cap
Thrombogenicity Thrombogenicity of the lipid coreof the lipid core
Illustration courtesy of Michael J. Davies, M.D.
CD40 and Tissue Factor in AtheromaCD40 and Tissue Factor in Atheroma
CD40
Mach F et al. Circulation 1997;96:396-399.
Tissue Factor
CD40 Ligation Induces Tissue Factor CD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived Expression in Human Monocyte-Derived MacrophagesMacrophages
Log Fluorescence
Cell
Nu
mb
ers
160
120
80
40
0
160
120
80
40
0100 101 102 103 100 101 102 103
rCD40L/-CD40L
rCD40L
T cell/membranes/-CD40L
T cell/membranes
Mach F et al. Circulation 1997;96:396-399.
CD40 ligand on activated platelets CD40 ligand on activated platelets
triggers an inflammatory reaction of triggers an inflammatory reaction of
endothelial cellsendothelial cells
Henn V et al. Nature 1998;391:591-594.
Inflammation Can Promote ThrombosisInflammation Can Promote Thrombosis
PlateletPlatelet
TissueTissueFactorFactor
FibrinogenFibrinogen
Via gp llb/lllaVia gp llb/llla
FibrinFibrinCD40LCD40LPlatelet-Platelet-
FibrinFibrinThrombusThrombus
FibrinopeptidesFibrinopeptides
PlateletPlatelet
Inflammation Participates in All Phases of Inflammation Participates in All Phases of Atherothrombotic DiseaseAtherothrombotic Disease
Lesion initiation
Lesion progression
Thrombotic complications
Slide Source:Lipids Onlinewww.lipidsonline.org
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