17. Atherosclerosis Flashcards
What cells remove arterial tissue?
Macrophages
What cells make arterial tissue?
Smooth muscle cells
List the potentially modifiable risk factors
o Smoking o Lipids o Blood Pressure o Diabetes o Obesity o Lack of Exercise
List the not modifiable modifiable risk factors
o Age
o Sex
o Genetic Background
What is the risk associated when you have 2 or 3 different risk factors?
The risk associated is multiplicated
Describe the distribution of atherosclerosis
It is not evenly distributed and tends to arise at specific places. E.g The bifurcation of the common carotid artery
Where do atherosclerotic lesions tend to appear?
On the outside of a bend. When the blood goes around a corner too quickly you get turbulent flow
Where do LDLs deposit?
In the subintimal space and binds to matrix proteoglycans
When LDLs accumulate what does it also bring?
Macrophages
What do the macrophages do in the subinitmal layer?
They eat up the endothelial fat and become foam cells.
What happens to the foam cells produced?
They leave the subintimal layer
What does the lesion accumulate as fat deposition continues?
Pools of extracellular lipid, eventually the macrophages can no longer cope.
What happens when the fat builds up further?
A core of extracellular lipid forms - The pool of fats coalesce and forms a large mass of fat
How does a fibrous thickening form in the atherosclerosis?
Inflammation irritates the interior of the plaque
What do macrophages produce in the subintimal space?
Growth factors
What is the effect of growth factors?
They stimulate smooth muscle cells to grow and divide to make more collagen
What happens when the plaque ruptures?
The lipid core communicates with the lumen stimulating clot formation
What is the layer effect in atherosclrosis?
This comes from repeat episodes of plaque destabilisation
What are the main cell types involved in atherosclerosis?
Vascular endothelial cells Platelets Monocyte-macrophages Vascular smooth muscle cells T Lymphocytes
What is the function of vascular endothelial cells in relation to atherosclerosis?
- Barrier function
- Leukocyte recruitment
What is the function of platelets in relation to atherosclerosis?
- Thrombus generation
- Cytokine and growth factor release
What is the function of monocyte-macrophages in relation to atherosclerosis?
- Foam cell formation
- Cytokine and growth factor release
- Major source of free radicals
- Metalloproteinases
What is the function of vascular smooth muscle cells in relation to atherosclerosis?
- Migration and proliferation
- Collagen synthesis
- Remodelling and fibrous cap formation
What is the function of T lymphocytes in relation to atherosclerosis
- Macrophage activation
They are activated by macrophages
What are the systems responsible for haemostasis
Clotting cascade
Platelet aggregation
What are foam cells?
Macrophages that have consumed fat or phagocytosed lipoproteins
What are matrix metalloproteinases?
They degrade major extracellular proteins such as collagen
What can abnormal vascular smooth muscle cells with an atherosclerotic plaque secrete?
Collagen
What is the function of collagen in atherosclerosis?
It contributes to the stabilisation of the plaque and fibrous cap
What are the main inflammatory cells in atherosclerosis?
Macrophages
What are the two main classes of macrophage?
Resident
Inflammatory
What is the function of inflammatory macrophages?
Adapted to kill microorganisms
What is the function of resident macrophages?
Mainly homeostatic:
o Suppress inflammatory activity
o Alveolar resident macrophages (surfactant lipid homeostasis)
o Osteoclasts (calcium and phosphate homeostasis)
o Spleen (iron homeostasis)
What are LDLs?
Low density lipoproteins
BAD cholesterol
Where are LDLs synthesised?
Liver
What is the function of LDLs?
Carries cholesterol from the liver to the rest of the body (including the arteries)
What are HDLs?
High density lipoproteins
Where is the function of HDLs?
Carries cholesterol from the peripheral tissues including the arteries back to the liver
How are oxidised/modified LDLs produced?
Free radical attack on LDLs
What is function of oxidised/modified LDLs?
They are highly inflammatory and toxic forms of LDL found in vessel walls
Describe the structure of an LDL
Consists of a monolayer with apoproteins on the surface
What is the function of apoproteins?
They tell the LDL where to go
Where are LDLs susceptible to modification?
In the subendothelial layer, where LDLs are trapped by binding to sticky matrix carbohydrates
What is another name for the fat cells which macrophages phagocytose?
Oxidised LDLs
What does the production of foam cells stimulate?
Chronic inflammation
What is familial hyperlipidaemia?
Autosomal recessive genetic disease where people have massively elevated cholesterol
What is familial hyperlipidaemia a failure of?
Failure to clear LDL from the blood
What is often formed in familial hyperlipidaemia
Xanthoma - accumualtion of foam cells on the skin
What are the clinical features of FH?
Xanthomas and Early atherosclerosis
What are scavenger receptors on macrophages?
A family of pathogen receptors that accidentally bind to oxidised LDLs
How does a macrophage react with arterial OxLDL?
With lower levels of arterial OxLDL macrophages can remove abnormal materials resulting in safe clearance and reverse cholesterol transport.
However with higher levels of OxLDL macrophages will activate ‘bug detector’ pathways leading to inflammation
What receptors are responsible for the ‘bug detector’ pathways?
macrophage scavenger receptors (A and B)
What does the scavenger receptor A bind to?
OxLDL and gram positive bacteria and dead cells
What does the scavenger receptor B bind to?
OxLDL and malaria parasites and dead cells
What do macrophages generate within plaques?
Free radicals
What do the free radials do?
They further oxidise lipoproteins
What are macrophages activated by?
Modified lipoproteins/free intracellular cholesterol
What do activated macrophages secrete?
o Cytokine mediators that recruit monocytes
o Chemoattractants and growth factors for VSMC
o Proteinases that degrade tissue (e.g. the fibrous cap)
o Tissue factor that stimulates coagulation on contact with blood
In atherosclerosis what happens to the foam cells?
They die by apoptosis by leave cytotoxic fat everywhere contributing to the lipid rich core of the plaque
What is NADPH oxidase?
It takes oxygen and reduces it to form a superoxide (O2-)
What is the superoxide used to form in macrophages?
Hypochlorous acid
What is hypochlorous acid?
It is extremely toxic and is what activated macrophages secrete
As the macrophages get further and further from the subendothelial layer what happens?
They get bigger and bigger bloated with fat until the fat comes out of solution forming fat globules killing the macrophage
What are cytokines?
Protein immune hormones that activate endothelial cell adhesion molecules
What is function of interleukin-1?
Upregulates vascular cell adhesion molecule-1 (VCAM-1)
What is the function of VCAM-1?
Mediates right monocyte binding
What occurs when there is reduced VCAM-1 and interleukin 1?
There is reduced atherosclorosis
What are chemoattractants?
Small proteins chemoattractant to monocytes. E.g Monocyte Chemoattractant protein-1 (MCP-1)
What does MCP-1 bind to?
Binds to a monocyte G-protein coupled receptor (CCR2)
What occurs when there is reduced MCP-1 and CCR2?
There is reduced atherosclerosis
What cell do macrophages recruit?
They recruit VSMC stimulate them to proliferate and deposit extracellular matrix
What does increased deposition of collagen do?
Strengthens and stabilises the plaque
How do macrophages recruit VSMC?
They release complementary protein growth factors
What are the two main growth factors released by macrophages?
Platelet derived growth factor
Transforming growth factor beta
What is the function of the platelet derived growth factor?
- VSMC chemotaxis
- VSMC survival - promotes survival of smooth muscle in the toxic environment
- VSMC division
- Attracts smooth muscle from the tunica media to the abnormal plaque
What is the function of transforming growth factor beta?
- Doesn’t keep them alive or make them divide but does stimulate increased collagen synthesis
- This promotes plaque stabilisation
What can influence VSMC to become the synthetic phenotype?
PDGF and TGF-beta
What is normal phenotype of VSMCs?
Large number of contractile filaments
Low number of matrix deposition genes
What is the synthetic phenotype of VSMCs (atheroclerotic)?
Low number of contractile filaments
Large amount of matrix deposition
How do macrophages affect the extracellular matrix?
They degrade plaque collagen
How do macrophages degrade plaque collagen?
Matrix metalloproteinases
What does the degradation of plaque collagen cause?
Weakens the fibrous cap so that it may rupture causing thrombus formation
What are the features of a rupture prone plaque?
1) Large soft eccentric lipid-rich necrotic core
2) Thin fibrous cap
3) Reduces VSMC and collagen content
4) Increased VSMC apoptosis
5) Infiltrate of activated macrophages expressing MMPs
What does a thin fibrous cap always mean?
Reduced collagen content
What is nuclear factor kappa B?
Transcription factor and master regulator of inflammation
What is nuclear factor kappa B activated by?
o Scavenger receptors
o Toll-like receptors
o Cytokine receptors
What does nuclear factor kappa B switch on?
o Matrix metalloproteinases
o Inducible nitric oxide synthase
