17 Atherosclerosis Flashcards
Q: What are the inflammatory cells that come into atherosclerotic plaques?
A: Macrophages
Q: How does the function of smooth muscle and macrophages vary in atherosclerotic plaques? (3)
A: Smooth muscle cells and macrophages have contrasting functions
Macrophages are there to remove arterial tissue
smooth muscle cells are there to make more arterial tissue
Smooth muscle cells protect plaque integrity, they make more tissue which strengthens the artery
Q: Which diseases are associated with atherosclerosis? (2) How has their occurrence changed?
A: ischaemic heart disease and cerebrovascular disease
have increased in the world disease burden ranking
Q: What are the potentially modifiable risk factors for atherosclerosis? (6) Not modifiable? (3) If you have two or three different risk factors then the risk associated is?
A: Smoking Lipids Blood Pressure Diabetes Obesity Lack of Exercise
Age
Sex
Genetic Background
MULTIPLICATED
Q: Describe the distribution of atherosclerosis in the body?
A: Atherosclerosis is NOT evenly distributed - it tends to arise at specific places such as the bifurcation of the common carotid artery
Q: In terms of bends in blood vessels. Where do athersclerotic lesions tend to appear? why? (3) how?
A: Blood flow in arteries is LAMINAR so the blood flows fastest in the middle of the vessel and slower around the outside
When the blood goes around a corner too quickly it sets up EDDYs (turbulent flow)
Therefore, atherosclerotic lesions tend to appear on the outside of a bend rather than on the inside
Q: How does atherosclerosis form and progress? (7)
A: 1. LDLs deposit in the SUBINTIMAL SPACE and binds to matrix proteoglycans (when LDL are too high- exceed regulated endocytotic capacity of endothelium cells)
- > Once the LDLs enter the subintimal layer, a chain reaction is established (oxygen free radicals attack LDLs)
2. lesion begins small and then LDLs accumulate which brings in macrophages
3. macrophages eat up the endothelial fat (take in oxidised LDLs) via scavenger receptors and become FOAM CELLS and remove themselves from the viscinity: macrophages are capable of removing fat from the artery wall - reverse cholesterol transport
(macrophages also release oxygen free radicals)
- The macrophages and endothelial cells produce growth factors that stimulate smooth muscle cells to grow, divide
Macrophages also secrete matrix metalloproteinases which degrade collagen in the artery wall
- smooth muscle cells make collagen = forms fibrous cap (SM cells may also accumulate lipids and form foam cell)
The inflammation (stimulated by T cells recruited by macrophages) irritates the interior of the plaque to form a fibrous thickening
- As fat deposition continues, the lesion accumulates pools of extracellular lipids (outside the macrophages) and the macrophages can no longer cope
- macrophages are overwhelmed by the intracellular fat so die by apoptosis and release the toxic lipids and macrophage tissue factor into the necrotic core -> soft core of extracellular lipids and necrotic macro.
Q: What will eventually occur to an atherosclerotic plaque? result? Describe the layering effect. (4)
A: Eventually the plaque will RUPTURE which allows the lipid core (which is thrombogenic) to communicate with the lumen and stimulate clot formation within the lumen
comes from repeat episodes of plaque destabilisation
small episodes of thrombus forming and then stopping
the thrombi form one after another
to narrow the lumen a little bit at a time
Q: Name the 5 cell types involved in the development of an atherosclerotic plaque.
A: Vascular endothelial cells
Platelets
Monocyte-macrophages
Vascular smooth muscle cells
T lymphocytes
Q: What’s the role of vascular endothelial cells in the development of an atherosclerotic plaque? (2)
A: Barrier function (eg to lipoproteins)
Leukocyte recruitment
Q: What’s the role of platelets in the development of an atherosclerotic plaque? (2)
A: Thrombus generation
Cytokine and growth factor release
Q: What’s the role of monocytes-macrophages in the development of an atherosclerotic plaque? (4) What do these cells become due to the abnormal inflammatory action in advancing lesions?
A: Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases= group of enzymes that are responsible for the degradation of most extracellular matrix proteins inc collagen
become an inappropriate source of free radicals
Q: What’s the role of vascular smooth muscle cells in the development of an atherosclerotic plaque? (3) What do these cells do in an abnormal artery with an atherosclerotic plaque?
A: Migration and proliferation
Collagen synthesis
Remodelling and fibrous cap formation
can synthesise and secrete COLLAGEN which contributes to the stabilisation of the plaque and fibrous cap
Q: What’s the role of T lymphocytes in the development of an atherosclerotic plaque?
A: Macrophage activation: T cells - the feedback of macrophages activates T cell and the activated T cells, in turn, activate macrophages
Q: What are the 2 systems responsible for haemostasis? What can they generate? (2)
A: Clotting Cascade
Platelet Aggregation
Platelet aggregation and the coagulation cascade generate normal clotting but they can also generate abnormal clotting (thrombosis)
Q: What are foam cells? Size? What happens to foam cells over time? End result?
A: (can be vascular smooth muscle cells)
Macrophages phagocytose modified lipoproteins when they enter the subendothelial layer
they start off small but as they get further and further in they get bigger and bigger
These foam cells end up getting very sick because they are bloated with fat
They become so bloated with fat that the fat comes out of solution forming fat globules within the macrophage which eventually kills it
Q: Which cells are a key source of free radicals? What is the role of FRs?
A: macrophages
immune system makes as part of the natural immune function to kill microbes
Q: When can macrophages cause injury to host tissue? What determines what type of macrophage develops? What are the 2 main classes of macrophages?
What do macrophages have that can modify naive LDL?
A: if they are activated excessively or inappropriately
regulated by combinations of transcription factors binding to regulatory sequences on DNA
There are TWO main classes of macrophages:
- Resident: mainly homeostatic = Suppress inflammatory activity
- Inflammatory: adapted to kill microorganisms
Macrophages have oxidative enzymes that can modify native LDL
Q: What do resident macrophages do? 3 examples.
A: Suppress inflammatory activity
Alveolar resident macrophages (surfactant lipid homeostasis)
Osteoclasts (calcium and phosphate homeostasis)
Spleen (iron homeostasis)
Q: Compare LDLs and HDLs. Good or bad? Include where one is synthesised? Role?
A: Low Density Lipoproteins (LDLs)
- BAD cholesterol
- Synthesised in the LIVER
- Carries cholesterol from the liver to the rest of the body (including the arteries)
High Density Lipoproteins (HDLs)
- GOOD cholesterol
- Carries cholesterol from the peripheral tissues including the arteries back to the liver (reverse cholesterol transport)
Q: In what way can LDLs be modified? AKA? (2) What type are found is vessel walls?
A: Due to action of free radicals on LDLs
Oxidised LDLs, Modified LDLs
Families of highly inflammatory and toxic forms of LDL found in vessel walls
Q: What are the primary structures of an LDL? (2)
A: LDL consists of a monolayer
It has a protein on the outside (apoproteins) which tells it where to go
Q: Describe the sub endothelial trapping of LDLs. (2) What are trapped LDLs susceptible to?
A: LDLs can leak through the endothelial barrier
Once inside the subendothelial layer, LDLs are trapped by binding to sticky matrix carbohydrates (proteoglycans)
The trapped LDLs are susceptible to modification
Q: What can modify trapped LDLs? How? (2) To form? What does this stimulate?
A: The LDLs become modified by FREE RADICAL ATTACK
The LDLs become oxidatively modified
The oxidised LDLs are then phagocytosed by macrophages to form foam cells
This stimulates CHRONIC INFLAMMATION
Q: What type of disease is Familial Hyperlipidaemia (FH)? What do people with this have? (2) What does this cause? Clinical features? (3)
A: Autosomal recessive genetic disease
massively elevated choleterol (20 mmol/L)
There is failure to clear LDL from the blood
Patients’ skin and their arteries contain deposits of fat with the accumulations of foam cells (when this happens in the skin it is called a xanthoma)
xanthomas and early atherosclerosis (if untreated, fatal myocardial infarction before the age of 20)
Q: What did Brown and Goldstein do? Discovery? (2) Led to?
A: Hunted for the gene for FH
Discovered the LDL receptors and found that expression of the LDLR is negatively regulated by intracellular cholesterol
They also found that cholesterol synthesis is negatively regulated by cellular cholesterol
This led to the rationale of statins (HMG-CoA Reductase Inhibitors)
Q: What does it mean to be a negative LDLR patient? What was deduced? (2) Now known that?
A: don’t have LDL receptors= macrophages continue to accumulate cholesterol
It was deduced that there is a SECOND LDL receptor (on the macrophages) which is not under feedback control in atherosclerotic lesions
This receptor was called the SCAVENGER RECEPTOR because it hoovers up chemically modified LDL (oxidised LDL)
It is now known that scavenger receptors are a family of pathogen receptors that accidentally bind to oxidised LDLs
Q: Arterial OxLDL deposits can have TWO different effects. What are they? (4,3)
A: -Interaction of OxLDL with macrophages can lead to the abnormal materials being scooped up by the macrophage
- and removed from the artery
- form of safe clearance and leads to reverse cholesterol transport
- is a form of homeostasis
In the second pathway,
- higher levels of OxLDL will activate bug-detector pathways
- pathogen pattern recognition pathways which have evolved to detect anything with fat in it that isn’t us
- inflammatory
Q: How do the 2 scavenger receptors differ? What are they both involved in?
A: A (CD204)- binds to OxLDL but evolved to bind to Gram positive bacteria and dead cells
B (CD36)- binds to OxLDL but also binds to malaria parasites and dead cells
bug detector pathways- way macrophages act in response to higher levels of OxLDL
Q: What do macrophages do with plaques? What activates them? to? (4) What happens to them in the end? contributes to?
A: Macrophages GENERATE FREE RADICALS that further oxidise lipoproteins
(Macrophages phagocytose modified lipoproteins and become foam cells)
Macrophages become activated by modified lipoproteins/ free intracellular cholesterol to express/secrete:
- Cytokine mediators that recruit monocytes
- Chemoattractants and growth factors for VSMC
- Proteinases that degrade tissue (e.g. the fibrous cap)
- Tissue factor that stimulates coagulation on contact with blood
Finally, the foam cells die by apoptosis which is usually a clean process but in atherosclerosis this is messy - there is cytotoxic fat everywhere which contributes to the lipid rich core of the plaque
Q: What do macrophages produce when trying to kill pathogens? (2) Similar molecule? What is involved in making both? (2)
A: hypochlorous acid (domestos (bleach)) which is extremely toxic and rapidly degrades the surface
Activating macrophages basically makes the macrophages secrete hypochlorous acid in the arteries (highlights a lot of the problems that happen in atherosclerosis)
Peroxynitrite - MORE UNSTABLE than HOCL and is formed from nitric oxide
MYELOPEROXIDASE - involved in making hypochlorous acid (HOCL) and peroxynitrite (HONOO)
-needs superoxide which sits at the top of a cascade to form the oxygen that goes into HOCL (hypochlorous acid) which happens by the action of myeloperoxidase from hydrogen peroxide and chloride
Q: What is the formula for superoxide? What is it? How does it form? What does it do?
A: SUPEROXIDE (O2-) = oxygen molecule with an extra negative charge which is extremely reactive
produced in macrophages- NADPH Oxidase takes oxygen and reduces it (adds an electron)
Superoxide sits at the top of a cascade of highly reactive oxygen species to form the oxygen that goes into HOCL (hypochlorous acid) which happens by the action of myeloperoxidase from hydrogen peroxide and chloride
Q: What produces cytokines? What are they? Example. Mice experiment?
A: Plaque macrophages (express inflammatory factors involved in monocyte recruitment)
protein immune hormones that activate endothelial cell adhesion molecules
Interleukin-1 - upregulates vascular cell adhesion molecule-1 (VCAM-1)
-VCAM-1 - mediates monocyte binding
Atherosclerosis is reduced in mice without IL-1 or VCAM-1
Q: What produces chemoattractants? What are they? Example. Mice experiment?
A: Chemoattractants - small proteins chemoattractant to monocytes
Monocyte chemoattractant protein-1 (MCP-1)
-MCP-1 binds to a monocyte G-protein coupled receptor (CCR2)
Atherosclerosis is reduced in MCP-1 and CCR2 deficient mice
Q: What do both chemoattactants and cytokines do?
A: Both these systems set up viscous cycles - monocytes secrete more chemoattractants for more macrophages to come to the endothelial cells
Blood monocytes bring in more macrophages
Q: What are the 2 main growth factors produced by macrophages involved in wound healing in atherosclerosis? (4,2)
A: Platelet derived growth factor PDGF
- 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
Transforming growth factor beta TGF- beta
- Doesn’t keep them alive or make them divide but does stimulate increased collagen synthesis
- The increased deposition of collagen strengthens and stabilised the plaque
Q: How do vascular smooth muscle cells vary from being normal medial to atherosclerotic? (2,2) What causes this change? (2) What is the secondary function of VSMCs?
A: normal medial/contractile:
- more contractile filaments
- less matrix deposition genes
PDGF, TGF- beta (produced by macrophages)- influence the VSMC to turn become the synthetic phenotype
athersclerotic/synthetic:
- more matrix deposition
- less contractile filaments
They have a secondary function where they can repair the damaged interior
Q: What are matrix metalloproteinases? role? How do they interact with one another? What is a consequence of their role? (3) May lead to? (2)
A: family of around 28 homologous enzymes produced by macrophages
proteolyse extracellular matrix//that degrade plaque collagen via mechanism based on Zinc
They activate each other in a cascade via proteolysis
This degradation weakens the fibrous cap -> once it becomes weak enough it ruptures -> triggers thrombus formation
This may lead to an occlusive thrombus and cessation of blood flow
Q: Describe the pathology of a ruptured plaque. (4)
A: ((normally the coronary artery would be defined by the internal elastic lamina))
This thrombus has arisen because of a crack
The physical crack in the superficial cap of the artery is full of activated macrophages
It also contains lots of small vessels which have erythrocytes within them
The small vessels have been the source of a second problem which is the bleed
Q: What are the characteristics of vulnerable stable plaques. (5)
A: ((Rupture prone plaques))
Large soft eccentric lipid-rich necrotic core
Thin fibrous cap (reduced collagen content goes hand in hand with a thin fibrous cap)
Reduced VSMC and collagen content (Matrix metalloproteinases degrade the collagen in the plaque making it weaker)
Increased VSMC apoptosis
Infiltrate of activated macrophages expressing MMPs
Q: How many main coronary arteries do we have? How do they begin? (2) then? (2) 2 further structures.
A: 3
To begin with they come off as the Right Coronary Artery and the Left Main Coronary Artery
The right coronary artery runs down the right atrioventricular sulcus and supplies most of the right side of the heart (mainly the right ventricles)
LEFT divides into the Left Anterior Descending and Left Circumflex
LAD supplies the anterior free wall and the septum
Left Circumflex supplies the left ventricular free wall
Q: What causes macrophage apoptosis? Describe. (4)
A: in part, because the OxLDL derived metabolites are TOXIC (e.g. 7-keto cholesterol)
Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
When they are finally overwhelmed by the amount of fat, they die by apoptosis
They release macrophage tissue factor and toxic lipids into the central death zone called the LIPID NECROTIC CORE
The thrombogenic and toxic materials accumulate in the lipid necrotic core until plaque rupture allows them to meet the blood
Q: What is Nuclear Factor Kappa B? (2) Activated by? (3) Function? (3)
A: Transcription Factor
Master regulator of inflammation
Activated by numerous inflammatory stimuli:
- Scavenger receptors
- Toll-like receptors
- Cytokine receptors
Switches on numerous inflammatory genes:
- Matrix metalloproteinases
- Inducible nitric oxide synthase
Q: Name 3 signs of a myocardial infarction.
A: severe pain, nausea and vomiting
