Pathogenesis of Atherosclerosis

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Pathogenesis of Atherosclerosis

• Judith Berliner, Ph.D.
• Departments of Pathology and Medicine
• Division of Cardiology
• David Geffen School of Medicine at UCLA

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Fatty Streak
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Early Fibrous Plaque
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Advanced Plaque
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Thrombus
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Ages of Progression Fatty Streak 0-30 Fibrous
Plaque 30-50 Complicated Plaque
40 Thrombosis 50
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Susceptible Sites (SS)
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Coronary Distribution of lesions
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Lipid Accumulation at Branches
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Flow Patterns
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Less Susceptible
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More Susceptible
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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

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E-NOS Low in More Susceptible Areas
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Antioxidant NrF2 is Activated in Non-Susceptible
Areas
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Inflammatory Molecules are Increased in
Susceptible Areas
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Early Fatty Streak
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Lipids Rapidly Accumulate
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Fatty Streak Formation
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• Fatty Streak
• Retention of LDL
• Entry of monocytes
• Foam cell formation

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Fatty Streaks Form in the Fetus of
Hypercholesterolemic Mothers
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Localization of Macrophages in Fibrous Plaques
Human coronary artery lesionImmunoperoxidase
with Mab to macrophages (HAM-56)
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Endothelial Morphology
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• Alterations in Endothelial Cells and Monocytes in
  Fatty Streak Lesions
• Endothelial cells display increased adhesion
  molecules and chemotactic factors. VCAM-1,
  MCP-1, IL-8.
• 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

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Effects of Leukocyte Trafficking Genes on
Atherosclerosis In Knockout Mouse Models
Defect Response M-CSF
less MCP-1, CCR2
less P, E selectin
less VCAM-1 less
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Macrophage Foam Cells
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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

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Effect of genes related to foam cell formation on
fatty streak formation

• Gene
• CD36
• SRA-1
• LOX-1
• Apo A1
• ABC-A1

• Effect
• Less
• Less
• Less
• More
• More

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Atheroma / Fibrous Plaque
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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.

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Smooth muscle cells migrate into the intima
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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

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Formation of the Necrotic Core
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• Role of Lymphocytes in Atherosclerosis
• 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.

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Complex plaque
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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

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Vasa Vasorum
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Angiostatin Decreases Lesions
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Small Thrombi
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Cell Death in the Intima
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Genes associated with formation of the complex
plaque

1. VEGF, angiogenesis
2. Regulators of thrombosis
3. Regulators of thrombolysis
4. Regulators of apoptosis

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Thrombosis
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Ruptured Thrombus
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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
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Proteases in the Plaque
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Genes regulating formation of thrombus

1. Metalloproteinase
2. Apoptotic factors
3. Regulators of clotting

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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

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Evidence that oxidative stress is important in
atherosclerosis

• Levels of ROS increased in atherosclerotic
  vessels
• Feeding of cholesterol stimulates ROS formation
• 3. Lipid oxidation products stimulate
• inflammation in vitro and in vivo

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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
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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

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Therapeutic Approaches

1. Decrease plasma cholesterol levels Statins
2. Increase HDL protein or its mimetics
3. Increase reverse cholesterol transport by
   activating LXR
4. Decrease the levels of angiotensin
5. Inhibit inflammation NFkB inhibitor, MCP-1
   inhibitor, PPAR gamma agonist.
6. Identify proatherogenic polymorphisms