atherosclerosis Flashcards
where is the most common site of atherosclerosis?/ disease associated with atherosclerosis?
coronary arteries: CHD
modifiable RISK factors
smoking
high lipid intake
diabetes
sedentary lifestyle
obesity
blood pressure
non mod risk factors
age
sex
genetics
how much does each risk factor incr ur risk? how much do all together?
most single: high cholesterol
hypertension
then smoking
if you have all three X13 times more likley to get atherosclerosis (its not direct products of single factor risk x)
what has changef in epidemeoology over last decade?
hyperlipidaemia and hypertension improved due to statin and antihypertensive treatment respectively
obesity increased
important improvements in diabetes however doubtful impact on macrovascular disease
changing pathology of coronary thrombosis related to altered risk factors
overall is atherosclerosis a greater or lesser global health burdain now>
greater
cell types involved in atherosclerosis pahtophysiology
blood cells: immune and non immune
-t lymphocytes,
-macrophages/ monocyte
-platelets
vessel cells:
-vascular smooth muscle cells
-vascular endothelial cells
what do vascular endothelial cells do
recruit leukocytes
barrier function- to lipoproteins
platelets role
thrombus generation
CYTOKINE and growth factor release!!!
T lymphocytes role
- CD4 t1: macrophage activation
- CD4 reg: macrophage deactivation
- CD8 killer - endothelial smooth muscle cells killing
- B-cell/ antibody help- CD4 Th2
macrophage role (overall- general version)
foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteinases
vascular smooth muscle cell role
fibrous cap formation + remodelling
collagen synthesis
migration and proliferation
what is a common misconception about the pathophysiology in atherosclerosis? what is the reality? what clinical evidence supports this?
-atherosclerosis has an inflammatory basis.
-:MULTIPLE MECHS INcluding cholesterol crystal formation
-ITS NOT passive lipid deposition in vessels. (fatberg).
-This is proven by patients with high risk of atheroscleross complications (stroke and heart attack) having fewer of those after being given antibodies to IL-1
what cell is mucrophage derived form
monocyte
how are different macrophage subtypes made/ regulated?
by combination of transcription factors binding to regulatory sequences on DNA. However we do not yet understand the regulation.
what are the 2 types of macrophages
inflammatory (adapted to kill microorganisms)
non-inflammatory and resident macrophages
-(normally homeostatic functions- parenchymal (=functional not structural))
-alveolar resident macrophages - surfactant lipid homeostasis
- spleen- iron homeostasis
function of ldls
bad cholesterol synthesized in liver
carries cholesterol from liver to rest of body (incl lung and arteries)
function of HDLS
good cholesterol, carries cholesterol from peripheral tissues incl arteries back to liver (reverse cholesterol transport!!!)
what shape curve is seen when stroke or myocardial infarction is on y axis and ldl conc on x?
LDL- C and J curve: means that stroke chance decr for first few levels of ldl incr ( we need some of it) but incr for further ldld conc incr (we all have too much ldl thats why its bad choletserol)
what are oxidised and modified ldls
Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
families of highly inflammatory and toxic forms of LDL found in vessel walls
what is the ldl surrounding composed of?
lipid monolayer
what is a docking molecule?
a molecule that lies embeded in the lipid monolayer of an LDL and acts as an address for where the ldl should be going
some docking molecules also interact with clotting and clotting factors
what parts of the LDL do free radicals attack>
lipid monolayer and docking molecule
Describe the process of ldl modification (ex. oxidation)
1) LDLs leak through endothelium in areas of -endothelial vortex-: due to endothelial activation in these areas
2) LDL becomes suscesptible to modifications by binding to sticky matrix carbohydrates (proteoglycans) in subendothelial layer
3) LDLs become oxidised after being attacked by free radicals
4) OXIDISED LDLs are phagocytosed by acitvated macrophages that are now called foam cells
this stimulates chronic inflammation
what is familial hyperlipidemia? FH. (nature of illness and main features seen)
1) genetic autosomal dominant with gene dosage (meaning if you have 1 allele you do have it but if you have 2 you have more intense)
2) very high levels of cholesterol (>20 mmol/ L vs 1-5mmol/L: normal)
3) xanthomas and early atherosclerosis
what is the risk of leavinf FH untreated?
fatal myocardial infarction before 20
what is the pathophysiology of FH (one line answer)
failure to clear LDLD from blood
what 2 things does cellular cholesterol negatively regulate?
LDL receptor expression and
cholesterol synthesis
what is the biochem name of statins and what do they do
HMG-CoA reductase inhibitors - they inhibit this enzyme which is involved in cholesterol synthesis in the liver
the discovery of which homeostatic cellular negative feedback loop helped in the discovery of statins and why?
discovery of the loop of: cholesterol synthesis being negatively regulated by cellular cholesterol
(because increased cellular cholesterol inhibits HMG-CoA reductase, thats how they got the idea of making an inhibitor for this enzyme: statins)
what happens in patients that are LDLR negative?
since ldl cant be scooped up by normal cells, macrophages accumulate cholesterol
what is a scavanger receptor? feedback control? location? what binds to it?
another type of LDL recepetor discovered after the main one.
1) not under feedback control
2) found in atherosclerotic lesions
3) bind OxLDL
4) later found out that they are pathogenic (not normal)
what is an other drug mechanism for lowering LDL levels?
PCSK9 inhibitors
PCSK9 is bad, degrades LDL receptors (leads to
1) more ldl in blood,
2) less ldl in cells which would lead to supressed cholesterol synthesis
when are PCSK9 inhibitors used?
PCSK9 inhibitors are used
1) as supplement to statins for severe hyperlipidemia or
2) for statin resistant hyperlipidemia
WHAT Forms can PCSK9 inhibitors be designed in?
Antibodies
Antisense
Si-RNA
what are ABCA? (ABCA1 and ABCG1)
-CHOLESTEROL EXPORT PUMPS:
-in macrophage membranes
- interact with apolipoprotein on HDLs
- removing cholesterol from arteries and initiating return to the liver
what cells are scavanger receptors found on?
macrophages
what is the biochem name of macrophage scavanger receptor A and where does it bind?
Known as CD204
-Binds to oxidised LDL
-Binds to Gram-positive bacteria!!!! like Staphylococci & Streptococci
-Binds to dead cells!!!!
what is the biochem name of macrophage scavanger receptor B and where does it bind?
-Known as CD36
-Binds to oxidised LDL
-Binds to malaria parasites!!!!
-Binds to dead cells
what is the response to arterial Ox-LDL deposits when there are scavanger receptors vs when there are not
with scavanger receptors LDLs bind on them on the macrophage and the “bug detector “ pathways are activated - infammation
note(:think abt the other things that bind on scavanger rec- pathogens and dead cells: infm responce trigger)
vs without scavanger, theres safe clearance reverse cholesterol transport- HDL production to transport cholesterol back to blood (ABCA pumps)
difference of cytokines vs chemokines in general (got it from online for personal clarity)
cytokines are signalling molecules in general
chemokines are specifically signalling molecules that help in recruitment of immune cells (get their name from chemotaxis: movement of a cell across a chem gradient)
examples of free radicals generated by macrophages to oxidise lipoproteins and the oxidising enzymes that form the radicals
1) NADPH Oxidase: enzyme that results in, superoxide O2-. formation
2) Myeloperoxidase : enzyme -catalyzes reaction between (H2O2) and(Cl-) to produce (HOCl) (radical)
or
myeloperoxidase can react with (NO) to form peroxynitrite (ONOO−) (radical)
3) Generation of H2O2
what protein is stained to see macrophages (in their foam cell phase) ? (what colour?)
macrophage specific protein: CD68: brown dye
what is dark brown?
foam cells
what is the light brown around?
foam cell debris- dead toxic stuff
what are the little clear circles inside foam cells?
fat globules
what are the clear random shaped zones around foam cell debris?
cholesterol crystals
what is the function of cytokines released by macrophages
they are protein “immune hormones”(-meaning the equivalent of a hormone for the immune system bc they signal..) that activate endothelial cell adhesion molecules
1 example of a macrophage released cytokine and proof that its involved in atherosclerosis pathophysiology
Interleukin-1
– triggers intracellular cholesterol crystals and NFkB. (ect.)
-Coordinates cell death and cell proliferation; and elevated CRP (ect.)
-Atherosclerosis is reduced in mice without IL-1 and humans with anti-IL-1 antibodies
macrophage derived chemokines role
small proteins chemoattractant to monocytes
example of chemokine, where it binds on monocyte and proof its involved in atherosclerosis pathophysiology
Monocyte chemotactic protein-1 (MCP-1)
binds to a monocyte G-protein coupled receptor CCR2.
Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice.
what is 1 bad side effect of cytokine and chemokine release
immunosupression (think- monocytes recruited..)
what is a problematic feature of cytokine and chemokine recruitment>
Positive feedback loop / vicious cycle leading to self-perpetuating inflammation.
(bc monocytes (the recruited cell) are the pre-form of macrophages..)
what are teh functions of platelet derived growth factors (one of the 2 types of gf for Vascular smooth muslce cells VSMC)
Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)
what are the functions of transforming growth factor beta factors?
Increased collagen synthesis
Matrix deposition
what are the effects of PDGF and TGF-b ON A VASCULAR SMOOTH MUSCLE CELL?
turns from normal conctractile medial cell
with high contractile filaments and low matrix deposition genes
to
atherosclerotic synthetic VSMC with low contractile filaments and high matrix deposition genes
what are metalloproteinases
Family of ~28 homologous enzymes.
how are metalloproteinases activated
Activate each other by proteolysis.
what do metalloproteinases do and what chemical element is their mechanism based on
Degrade collagen.
Catalytic mechanism based on Zn.
what is the effect of plaque errosion/ rupture?
Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.
what happens to pacrophages (foam cells) once they are overwhelmed and why
even though macrophage foam cells have protective mechanisms that mentain survuval in face of toxic lipid loading, they can become overwhelmed at some point due to oxLDL-derived toxic metabolites such as 7 keto-cholesterol
die via apoptosis
what happens when macrophages have nbeen apoptosed
Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
this Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.
what does it mean that NFKb IS A NON REDINDANT NETWORK IN INFLAMMATION
it means that NF-κB plays a unique and essential role in regulating the inflammatory response, and its functions are not easily replaced or duplicated by other signaling pathways.
WHAT IS NFkB?
NUCLEAR FACTOR KAPPA b
A TRANSCRIPTION FACTOR that directs multiple inflammatory genes based on multiple different inflammatory stimuli
examples of inflammatory stimuli acting on NFkB and the inflammatory genes regulated
Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1
cholesterol signals
examples of inflammatory genes regulated by NFkB
Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1
