Pathogenesis of
Atherosclerosis
Judith Berliner, Ph.D.
Departments of Pathology and Medicine
Division of Cardiology
David Geffen School of Medicine at UCLA
Fatty Streak
Early Fibrous Plaque
Advanced Plaque
Thrombus
Ages of Progression
Fatty Streak – 0-30
Fibrous Plaque – 30-50
Complicated Plaque – 40+
Thrombosis – 50+
Susceptible Sites (SS)
Coronary Distribution of
lesions
Lipid Accumulation at Branches
Flow Patterns
Less Susceptible
More Susceptible
Nitric Oxide Function
(anti-inflammatory)
• Causes smooth muscle cell relaxation
(vasodilation)
• Suppresses SMC proliferation and matrix
synthesis
• Reduces the expression of inflammatory
genes
• Inhibits platelet aggregation
E-NOS Low in More Susceptible Areas
Antioxidant NrF2 is Activated in NonSusceptible Areas
Inflammatory Molecules are Increased in Susceptible Areas
Early Fatty Streak
Lipids Rapidly Accumulate
Fatty Streak Formation
Fatty Streak
1. Retention of LDL
2. Entry of monocytes
3. Foam cell formation
Fatty Streaks Form in the Fetus of
Hypercholesterolemic Mothers
Localization of Macrophages in Fibrous Plaques
Human coronary artery lesion
Immunoperoxidase with Mab to macrophages (HAM-56)
Endothelial Morphology
Alterations in Endothelial Cells and Monocytes in Fatty
Streak Lesions
1. Endothelial cells display increased adhesion
molecules and chemotactic factors. VCAM-1,
MCP-1, IL-8.
2. In fat feeding there is an increase in the
number of monocytes in the blood and a
change in the ratio of subtypes.
3. Monocytes become more adhesive for
endothelium.Only specific monocyte subtypes
enter the vessel wall: GR1/ly6C hi
Effects of Leukocyte Trafficking Genes on
Atherosclerosis In Knockout Mouse Models
Defect
M-CSF
MCP-1, CCR2
P, E selectin
VCAM-1
Response
less
less
less
less
Macrophage Foam Cells
Foam Cell Formation
1. Normal LDL does not cause foam cell
formation
2. Aggregated LDL-taken up by the LDL
receptor
3. Oxidized LDL-taken up by scavenger
receptors CD 36, SRA-1, LOX-1
4. Sphingomyelinase modified LDL-taken up by
scavenger receptors
5. Foam cell formation is inhibited by HDL
6. Foam cells accumulate near the EC
Effect of genes related to foam cell
formation on fatty streak formation
Gene
Effect
CD36
Less
SRA-1
Less
LOX-1
Less
Apo A1
More
ABC-A1
More
Atheroma / Fibrous Plaque
Fibrous Plaque
1. Cytokines produced by macrophages lead to
SMC migration and proliferation
2. SMC proteases digest elastic lamina to aid
migration of SMC into the intima
3. SMC synthesize collagen and specific
proteoglycans
4. SMC take up lipid forming foam cells
5. SMC and monocytes die by apoptosis or
necrosis liberating cell contents.
6. Lymphocytes enter the lesion.
Smooth muscle cells migrate into the intima
Effect of genes related to SMC migration,
proliferation, matrix synthesis and death of
foam cells on plaque formation
Gene
PDGF
IL-1beta
FGF
Effect on atherogenesis
Less
Less
Less
Formation of the Necrotic Core
Role of Lymphocytes in Atherosclerosis
1. T cells, mainly of Th-1 subtype,enter the
vessel. They produce high levels of gamma
interferon.Knockout of gamma in mice
decrease atherosclerosis.
2.B1b cells are increased. B1b are innate
immune cells that make antibodies to oxidized
lipids which also react with bacteria. They may
serve a protective function.
Complex plaque
Characteristics of the complex plaque
1. Accelerated cell death and growth of necrotic core
2. Angiogenesis
3. Formation of small thrombi on lumenal surface
4. Hemorrhage from newly formed vessels
5. Incorporation of thrombi and clots into vessel wall
Vasa Vasorum
Angiostatin Decreases Lesions
Small Thrombi
Cell Death in the Intima
Genes associated with formation of the
complex plaque
1.
2.
3.
4.
VEGF, angiogenesis
Regulators of thrombosis
Regulators of thrombolysis
Regulators of apoptosis
Thrombosis
Ruptured Thrombus
Effectors of Thrombus formation
1. Endothelium
Promoters of thrombosis
Promoters of thrombolysis
2. Macrophages
Produce tissue factor
Necrotic core contains tissue factor
3. Platelets
Show increased reactivity in atherosclerosis
Proteases in the Plaque
Genes regulating formation of
thrombus
1. Metalloproteinase
2. Apoptotic factors
3. Regulators of clotting
Initiators of Atherogenesis:
Lipoproteins: LDL and VLDL
Oxidative Stress: Lipid oxidation, activation of inflammation
Hypertension: Angiotensin and alteration in NO
Diabetes: Hypertension and glycosylated proteins
Smoking and pollutants: Oxidative stress
Evidence that oxidative stress is
important in atherosclerosis
1. Levels of ROS increased in
atherosclerotic vessels
2. Feeding of cholesterol stimulates
ROS formation
3. Lipid oxidation products stimulate
inflammation in vitro and in vivo
4. Risk factors such as glucose,
AII and smoking increase ROS
5. Accumulation of oxidized lipids in
lipoproteins is prognostic
6. Exposure of platelets to oxidized
lipids causes activation
7. Antioxidant enzymes are protective
Atherogenic gene polymorphisms in
humans associated with oxidation
1. CD 36
2. Paraoxonase
3. Platelet Activating Factor Acetyl Hydrolase
4. HO-1
5. Glutathione Transferase
6. Glutathione Synthase
Therapeutic Approaches
A. Decrease plasma cholesterol levels
– Statins
B. Increase HDL protein or its mimetics
C. Increase reverse cholesterol transport
by activating LXR
D. Decrease the levels of angiotensin
E. Inhibit inflammation: NFkB inhibitor,
MCP-1 inhibitor, PPAR gamma agonist.
F. Identify proatherogenic polymorphisms