Atherosclerosis Flashcards
What are the risk factors of atherosclerosis?
Modifiable - smoking, lipids, BP, diabetes, obesity, lack of exercise
Non modifiable - age, sex and genetics
Why does atherosclerosis occur at certain areas like the common carotid artery?
Atherosclerosis occurs where the common carotid artery bifurcates. Blood flow becomes turbulent rather than laminar after turning a corner fast so plaques are outside a bend
Where do LDLs deposit and what do they bind to?
In the subintimal space and they bind to matrix proteoglycans. Here they are susceptible to infection
How does atherosclerosis progress?
- LDLs enter the subintimal space
- LDLs accumulate and macrophages eat the endothelial fat and become foam cells
- Fat deposits and extracellular lipids which macrophages cannot remove all of
- Core of extracellular lipid forms
- Macrophages release GF to stimulate smooth muscle cells to make collagen, divide and grow
- Plaque ruptures
- Thrombogenic lipid core stimulates clot formation in lumen
- repeat episodes cause layers to form
What is atherosclerosis?
Artery disease in which plaques form in the vessel walls
What do vascular endothelial cells do?
- they are barries e.g. to lipoproteins
- they recruit leukocytes
What do platelets do?
- Produce thrombus
- Release cytokines and GF
What do T lymphocytes do?
They activate macrophages, and macrophages activate T cells
What do macrophages do?
- foam cell formation
- release cytokines and GF
- Source of free radicals
- source of metalloproteinases
MAIN INFLAMMATORY CELLS IN ATHEROSCLEROSIS
What do vascular smooth muscle cells do?
- synthesis collagen to stabilise plaque
- remodelling and fibrous cap formation
- migration and proliferate
What are the 2 systems involved in haemostasis?
clotting cascade
platelet aggregation
What are the two main classes of macrophages?
- resident (adapted to kill microorganisms)
- inflammatory (homeostatic)
What do matrix metalloproteinases do? How can they lead to thrombus formation?
They degrade major extracellular proteins like collagen - activate each other in a cascade. Mechanism based on zinc. Degradation of collagen weakens fibrous cap and it can rupture to form a thrombus
What do macrophages produce as part of the normal immune response and why is it bad during atherosclerosis?
Macrophages secrete cytokines and growth factors and are a key source of free radicals which the immune system makes as part of the natural immune function to kill microbes. Becomes excess source in atherosclerosis though
What do inflammatory macrophages do?
- suppress inflammation
- include osteoclasts, alveolar resident macrophages (surfactant lipid surfhomeostasis), in the spleen involved in iron homeostasis
What are the different types of lipoproteins, what do they do?
- LDL - bad, made in liver and carry cholesterol from liver to body
- HDL - good, carry cholesterol from periphery to liver
- oxidised LDL,modified LDL - due to action of free radicals on LDLs, family of highly inflammatory/toxic LDL in vessel walls
What is the structure of LDL?
It is a lipid monolayer, has apoproteins on outside (tells it where to go). It has TG and CE in core
How are LDLs modified in the sub-endothelial and how does this lead to chronic inflammation?
In the sub-endothelial layer, LDLs are modified by free radicals (oxidised). Macrophages phagocytose them (become foam cells) and this stimulates chronic infllammation
What is familial hyperlipidaemia?
- recessive
- high cholesterol
- LDL can’t be removed from the blood
- Skin and arteries have fat deposits with foam cells accumulated
What are the clinical features of familial hyperlipidaemia?
- early atherosclerosis
- xanthomas (foam cell accumulation in skin)
- can lead to MI before age 20
How is LDLR expression regulated?
How is cholesterol synthesis regulated?
LDLR expression is negatively regulated by intracellular cholesterol. Cholesterol synthesis is negatively regulated by cellular cholesterol
What is a scavenger receptor?
LDL receptors. They are on macrophages and were initially pathogen receptors but can also bind to oxidised LDLs
What does a macrophage scavenger receptor A do?
binds oxidised LDL, binds Staphylococci & Streptococci, and dead cells
What does a macrophage scavenger receptor B do?
Binds to oxidised LDL, malaria and dead cells
What does the macrophage do to the arterial Ox-LDL deposits?
If there is OxLDL, then they are removed from the artery. If there are very high high levels of OxLDL, they activate a bug detector pathway (scavenger receptor A and B).
What are macrophages activated by in the plaques?
What do they secrete?
Macrophages are activated by modified lipoproteins/free intracellular cholesterol to:
- secrete cytokines that recruit monocytes
- secrete chemoattractants and growth factors for VSMC
- express proteinases that degrade tissue (e.g. the fibrous cap)
- secrete tissue factor that stimulates coagulation on contact with blood
How do foam cells die?
Apoptosis - in atherosclerosis it isn’t clean but messy as fat goes everywhere
What does NADPH oxidase do (macrophage enzyme)?
Reduces oxygen to make a superoxide (O2^-) which is reactive
What is superoxide used to produce, which enzyme catalyses it, and what are the reactants?
Superoxide is used to form HOCL (hypochlorous acid) catalysed by myeloperoxidase from hydrogen peroxide and chloride
What is peroxynitrite?
Made from nitric oxide radical and superoxide. It is more unstable than HOCL
What is myeloperoxidase and what does it do?
Enzyme involved in making hypochlorous acid (HOCL) and peroxynitrite (HONOO)
What are the characteristics of vulnerable (opposite to stable) plaques?
- large, soft, lipid-rich necrotic core
- thin fibrous cap
- reduced VSMC and collagen
- increased VSMS apoptosis
- infiltration of activated macrophages expressing MMP (matrix protein)
How does macrophage apoptosis occur -describe the process?
- OxLDLs are toxic
- They have protective systems but can be overwhelmed by amount of fat. They release macrophages tissue factors and toxic lipids in to the central death zone called the lipid necrotic core. The thrombogenic and toxic materials accumulate until plaque ruptures
What is nuclear factor kappa B? What activates it? What does it do?
- TF
- Regulates inflammation
- activated by scavenger receptors, toll like receptors, cytokine receptors.
- activates matrix metalloproteinases and inducible nitric oxide synthase
What is the secondary function of VSMCs?
- they repair damaged vessels
- PGDF and TGF - beta can influence VSMCs to become synthetic so they switch from contractile and make ECM
What are the two main growth factors that macrophages make that are involved in healing of atherosclerosis?
- Platelet derived growth factor = VSMC chemo-taxis, survival, division and attracts them from tunica media to plaque
- Transforming growth factor beta = stimulates collagen synthesis to stabilise plaque
What inflammatory mediators do plaque macrophages secrete to recruit monocytes?
- cytokines = interleukin 1 (up-regulates VCAM-1), VCAM-1 (mediates monocyte binding)
- Chemo attractants = small proteins that attract monocytes. E.g. MCP -1 (binds to a G coupled receptor)
Monocytes then secrete more chemo-attractants for more macrophages to come to the site
What do macrophages produce to kill pathogens?
hypochlorous acid (bleach), which is toxic and rapidly degrades the surface
