17. Atherosclerosis Flashcards
What types of blood vessels does atherosclerosis affect?
Medium and large arteries
When does atherosclerosis start to progress and how does this affect prevention?
- Changes in arteries early in life
- Plenty of time for prevention
- Clinical manifestations in middle and old age
What is the significance in the role of the macrophages compared to smooth muscle cells in atherosclerosis?
- Macrophages - remove arterial tissue
* Smooth muscles - make more arterial tissue and protect plaque integrity
What are potentially modifiable risk factors for atherosclerosis?
- Smoking
- Blood pressure
- Diabetes
- Obesity
- Lack of exericise
What are non-modifiable risk factors for atherosclerosis?
- Age
- Sex
- Genetic background
Why do atherosclerotic lesions tend to appear on the outside of a bend?
- Blood flow is laminar - faster in the middle
- Blood goes around a bend - EDDYs (turbulent flow) is set up
- Less flow on the outside
Where do LDLs deposit in the arteries?
- Subintimal space
- Bind to matrix proteoglycans in the subendothelial layer
- Become susceptible to modification
How does atherosclerosis progress from the deposition of LDLs?
- Inflammation (adaptive)
- Macrophages ingest the endothelial fat - become foam cells
- Extracellular lipids build up forming a core
- Fibrous thickening - due to inflammation irritating the interior of the plaque
- Macrophages produce growth factors - stimulate smooth muscle cells to grow, divide and make more collagen
- Plaque ruptures - lipid core (thrombogenic) communicates with the lumen and stimulates clot formation
- Layering effect - repeat episodes of plaque destabilisation
- Thrombi form one after the other - lumen narrows and becomes too small
- Angina or MI
What is the basic function of vascular endothelial cells?
- Barrier (e.g. to lipoproteins)
* Leukocyte recruitment
What activates the macrophages?
T lymphocytes
What are matrix metalloproteinases and what forms them?
- Enzymes that grade major extracellular proteins e.g. collagen
- Produced by macrophages
What are the main inflammatory cells in atherosclerosis?
- Macrophages
* Several subtypes - regulated by a combination of transcription factors
What are the 2 main classes of macrophages?
- Resident - homeostatic, suppress inflammatory activity
* Inflammatory - adapted to kill microorganisms
What are oxidised LDLs?
- Formed by action of free radicals (from macrophages) on LDLs
- Families of highly inflammatory and toxic forms of LDL in vessel walls
What part of the LDL directs it and can be detected?
Apoproteins
What is Familial Hyperlipidaemia?
- Autosomal recessive
- Elevated cholesterol
- Failure to clear LDL from the blood
- Accumulation of foam cells - xanthoma in the skin
- Early atherosclerosis => fatal MI before the age of 20 if untreated
What were Brown and Goldstein’s findings?
- Looked for the gene for Familial Hyperlipidaemia
- Discovered LDL receptors
- Found that their expression was negatively regulated by intracellular cholesterol
- Also found that cholesterol synthesis is negatively regulated by cellular cholesterol
- Led to the rationale of statins
What is the scavenger receptor?
- Second LDL receptor on macrophages
- Not under feedback control
- Accidentally binds to and takes up oxidised LDL
- Macrophages accumulate cholesterol
What is Macrophage scavenger receptor A?
- CD204
- Binds to oxidised LDL
- Binds to gram-positive bacteria
- Binds to dead cells
What is Macrophage scavenger receptor B?
- CD36
- Binds to oxidised LDL
- Binds to malaria parasites
- Binds to dead cells
What are the 2 different effects of arterial oxidised LDL deposits?
1) Interaction with macrophages - abnormal material removed safely
2) High levels of oxidised LDL - bug-detector pathways activated (scavenger receptors) - pathogen pattern recognition pathways activated, detect anything with fat in it that isn’t us - inflammatory
What do activated macrophages secrete?
- Cytokine mediators - recruit monocytes
- Chemoattractants and growth factors for VSMCs
- Proteinases - degrade the fibrous cap
- Tissue factor - stimulates coagulation
How do the macrophages contribute to the lipid rich core?
- Apoptosis - usually clean
* Cytotoxic fat everywhere in atherosclerosis
How do macrophages modify LDL with oxidative enzymes?
- Macrophages take oxygen and reduce it (add electron) [NADPH oxidase]
- Form a reactive superoxide (O2-)
- Cascade - hydrogen peroxide + chloride => hypochlorous acid (HOCL) [myeloperoxidase]
- HOCL is extremely toxic
- Nitric oxide can form peroxynitrite (HONOO) which is even more unstable [myeloperoxidase]
What happens to macrophages as they accumulate fat?
- Start off small
- Foam cells
- Bloated with fat
- Fat comes out of the solution - fat globules within the macrophages kill it
Which cytokines do macrophages express and what are their roles in the arteries?
- Interleukin-1 - upregulates vascular cell adhesion molecule-1 (VCAM-1)
- VCAM-1 - mediates right monocyte binding
- Lead to a viscous cycle (positive feedback)
(atherosclerosis is reduced in mice without these cytokines)
Which chemokines do macrophages express and what are their roles in the arteries?
- Monocyte chemoattractant protein-1 (MCP-1)
- MCP-1 binds to a monocyte G-protein coupled receptor CCR2
- Lead to a viscous cycle (positive feedback)
(atherosclerosis is reduced in mice without these chemokines)
How do macrophages stabilise the plaque?
• Macrophages release complementary growth factors that recruit VSMCs
- Platelet derived growth factor (VSMC chemotaxis, survival and division)
- Transforming growth factor beta (increased collagen synthesis)
• Proliferation and deposition of extracellular material strengthens and stabilises the plaque
How do VSMCs change to a synthetic phenotype?
- PDGF and TGF-beta influences the change
* These atherosclerotic VSMCs make more ECM and have fewer contractile filaments
How do metalloproteinases work?
- (Matrix) metalloproteinases activate each other in a cascade
- Mechanism is based on zinc
- Degrade collagen
- Weakens the fibrous cap - triggers rupture and thombus formation
- Instant thrombosis when material meets blood - occlusive thrombus
Which border normally defines the coronary artery?
Internal elastic lamina
What are the characteristics of stable, rupture prone plaques?
- Large, soft, eccentric, lipid-rich necrotic core
- Thin fibrous cap
- Reduced VSMC and collagen content (VSMC apoptosis)
- Infiltrate of activated macrophages expressing MMPs
What are the 3 main coronary arteries?
• Right Coronary Artery - runs down the right atrioventricular sulcus
• Left Main Coronary Artery
- Left Anterior Descending: supplies the anterior free wall and septum
- Left Circumflex: supplies the left ventricular free wall
What do macrophages do when they apoptose?
- Release macrophage tissue factor and toxic lipids into the lipid necrotic core
- Accumulation of materials inside core
What is endothelial erosion?
- Loss of endothelial cells
- Thrombosis occurs within the thick fibrous cap whilst the endothelial cells die
- Less pronounced inflammatory infiltrated
- Less association with a lipid/fatty core
- Non-occlusive mural thrombus
What is Nuclear Factor Kappa B?
• Transcription Factor • Master regulator of inflammation • Activated by: - Scavenger receptors - Toll-like receptors - Cytokine receptors • Switches on: - matrix metalloproteinases - inducible nitric oxide synthase (for peroxynitrite)
Why do endothelial cells become more sticky when activated?
Attract more monocytes => macrophages
What are 4 of the harmful functions of macrophages?
- Release free radicals
- Recruit more monocytes
- Express MMPs - destabilise the fibrous cap
- Express tissue factor - stimulates thrombosis
