PVD and Atherosclerosis Flashcards
What are modifiable risk factors in atherosclerosis development
Smoking Lipid intake BP Diabetes Obesity Sedentary lifestyle
What are non modifiable risk factors in atherosclerosis development
Age
Sex
Genetic background
How much do risk factors increase risk of developing atherosclerosis?
A lot, the risk also severely increases when multiple risk factors are involved
What layer does atherosclerosis start in?
Tunica intima
What are the stages of atherosclerosis progression called?
Coronary artery at lesion prone location Type 2 lesion Preatheroma Atheroma Fibroatheroma Complicated lesion
At what stage of atherosclerosis progression do foam cells form?
Type II lesion
What is the role of vascular endothelial cells in atherosclerosis
Barrier function (eg to lipoproteins Leukocyte recruitment
What is the role of monocyte/macrophages in atherosclerosis?
Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases
What is the role of platelets in atherosclerosis?
Thrombus generation
Cytokine and growth factor release
What is the role of platelets in vascular smooth muscle cells?
Migration and proliferation
Collagen synthesis
Remodelling and fibrous cap formation
What is the role of T lymphocytes in atherosclerosis?
Macrophage activation
What are the main inflammatory cells in atherosclerosis?
Macrophages
What are macrophages derived from in atherosclerosis?
Monocytes
What are the 2 main types of macrophages?
Inflammatory
Resident
What do inflammatory macrophages do?
They are adapted to kill microorgansims
What so resident macrophages do?
They are normally homeostatic and suppress inflammatory activity
What is the role of macrophages in the alveoli?
They are for surfactant lipid homeostasis
What is the role of macrophages in the osteoclasts?
For calcium and phosphate homeostasis
What is the role of macrophages in the spleen?
Iron homeostasis
Where is LDL synthesised?
In the liver
What is the role of LDL
Transport of cholesterol from the liver to the rest of the body (its bad cholesterol)
What is the role of HDL
Reverse cholesterol transport (from the body back to the liver)
What type of LDL is highly inflammatory and toxic
Oxidised or modified LDL
How is LDL trapped in the subendothelial space?
It binds to sticky carbohydrates in the matrix eg proteoglycans
What happens to LDL in the subendothelial space?
After becoming oxidised it is phagocytosed by macrophages and stimulates chronic inflammation
How is familial hypercholesterolaemia inherited?
Autosomal
What happens in familial hypercholesterolaemia and why?
Cholesterol becomes massively elevated due to deficiency of the LDL receptor in the liver
What does a deficiency of LDL receptors in the liver cause (eg in FH)?
Causes macrophages to accumulate cholesterol
What cholesterol level illicits recommendation for statins?
Above 5 mmol/L
What is cholesterol level in FH?
Above 20 mmol/L
How does FH present?
Xanthomas and early atherosclerosis
What is the second LDL receptor in atherosclerotic lesions called?
Scavenger receptors
What do scavenger receptors do?
They mop up chemically modified LDL
What do statins inhibit?
HMG coA reductase
What are the 2 types of scavenger receptors?
A and B
What do type A scavenger receptors bind to?
Oxidised LDL
Gram positive bacteria
Dead cells
What do type B scavenger receptors bind to?
Oxidised LDL
Malaria parasites
Dead cells
How do macrophages oxidise LDLs?
They have oxidative enzymes
What oxidative enzymes do macrophages contain?
NADPH oxidase
Myeloperoxidase
How do macrophages in plaques recruit monocytes?
They express cytokine mediators
What do cytokines do in atherosclerosis?
They activate endothelial cell adhesion molecules
What do chemokines do in atherosclerosis?
They are chemoattractants
to monocytes
Describe how inflammation in atherosclerosis is a positive feedback loop?
Cytokines and chemokine release increases the release of other cytokines and chemokines, so there is a vicious cycle leading to self perpetuating inflammation
For what type of cells do macrophages in plaques display chemo attractants and growth factors?
Vascular smooth muscle cells
What do vascular smooth muscle cells do once they have been recruited by macrophages in atherosclerosis?
They proliferate and deposit extracellular matrix
What states are vascular smooth muscle cells normally and then when they become athersclerotic?
Normally they are contractile, they then become synthetic
What causes the change from contractile to synthetic in vascular smooth muscle cells?
PDGF (platelet derived growth factor) and TGF-b (transforming growth factor beta)
What does PDGF do?
It causes:
VSMC chemotaxis
VSMC survival
VSMC division (mitosis)
What does TGF- beta do?
Increased collagen synthesis
Matrix deposition
What happens to contractile filaments and matrix deposition genes when VSMC switch from contractile to synthetic?
Contractile filaments go from high to low in number
Matrix deposition genes go from silent to being upregulated
What do proteinases displayed by macrophages in plaques do?
They degrade tissue and plaques, eventually this leads to plaque erosion or rupture (can lead to occlusive blood flow and death)
What is an example of a proteinase displayed by macrophages in plaques?
Metalloproteinases
What is the lipid necrotic core?
Central death zone where macrophages release tissue factors and toxic lipids
What is nuclear factor kappa B?
A transcription factor that is a master regulator of inflammation
What is nuclear factor kappa B activated by?
Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1
What genes does nuclear factor kappa B switch on?
Inflammatory genes eg
Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1
