cardiovascular diseases - atheroschlerosis Flashcards
what is the difference between atheroschlerosis and arterioschlerosis
both are the hardening of arteries but atheroschlerosis is narrowing and hardening due to a fatty plaque
why is (AS) considered an underlying factor to CVD?
AS can occlude the blood vessels of the corony artery leading to ischemia of the myocardial tissue -> myocardial infarction
also if plaque/thrombus ruptures can lead to embolus which can persist in circulation
what is the name given to CVD that affects the blood supply to the brain, heart, limbs/other organs?
cerebrovascular disease
CVD/ coronary artery
peripheral vascular disease
what are the components of a atheroschlerotic plaque?
oxidized cholesterol/ oxidised LDL
foam cells - dead macrophages
calcium crystals - contributes to the hardening of vessel
fibrous deposits from VSMC
NEED TO FACT CHECK
what are the ranges of high LDL level and low serum HDL level in mg/dL?
high LDL considered above 190mg/dL
low HDL considered below 40mg/dL
serum cholesterol level above 330mg/dL
what is a lipoprotein?
means of transporting lipids around the body, can be transported depending on fat:protein ratio
> fat has lower density than protein
also depends on which surface apoliprotein is present
HDL , LDL, VLDL, chylomicron
name some risk factors for AS
- irritants in the circulation
can be lifestyle things which we can change - diet high in LDL, sedentary (obesity), high BP, excess alcohol, smoking
things we cant change - genetic predisposition, age, gender (males more at risk)
cumulative effect of risk factors can increase your risk 16fold! (poulter et al 1993) - if you had all 3 of hypertrnsiton, high cholestrol and smking
compare and contrast the 2 mechanisms of lipid transport in human body
both exogenous and endogenous pathways use ‘‘lipoprotein lipase’’ to release FFA+glycerol from the lipoprotein providing energy or fat storage to peripheral tissues
differ in the source of fat (diet or liver) and the lipoprotein used to transport - chylomicron and some LDL or VLDL
describe how intracellular cholesterol levels can be regulated
(in response to HIGH cholesterol)
done primarily by negative feedback regulation
> too much i cholesterol is toxic so different genes are up and down regulated
HMG reductase (acetylCoA+ acetoacetylCOa->cholesterol) and LDL receptor gene down-regulated ACAT gene up-regulated so cholesterol is re-esterified and stored as a droplet so cant damage cell
what component of the lipoprotein do LDLR recognise? What happens after recognition?
they recognise the apolipoprotein lipase on surface of lipoproteins
when lipoprotein undergoes receptor mediated endocytosis, it forms an endosome
lysosome hydrolytic enzymes degrades components using acid.
this acid then dissociates the LDLR from LDL and allowing receptor to be recycled and re-fuse with the cell membrane
what is meant by reverse cholesterol transport?
it is a term used to describe the excretion of excess cholesterol as bile from peripheral tissues. This is mediated by HDL which transports excess cholesterol to the liver to be excreted/ removed from body
whereas normally cholesterol travels from liver to cells/tissues via LDL
what areas of blood vessels are atheroschlerotic plaques more likely to form?
Areas where there is turbulent flow and low shear stress- e.g. at bifucation sites. This is because on these areas, the morphology of endothelial lining is dysfunctional and LDLs can build up in these areas as there is low shear stress compared to areas with laminar flow.
Briefly describe the inital process of atherosclerosis
LDL enters the tunica intima layer of blood vessel. It becomes oxidised as the antioxidant effects of blood plasma are no longer present
this then activates endothelial cells to express cell adhesion molecules (eselectin, ICAM-1) to recruit macrophages
macrophages enter the tunica intima by diapedisis and macrophages use the pattern recognition receptors ‘‘scavenger receptors’’ to engulf oxLDL
why is AS considered an inflammatory disease?
scavenger receptors expressed on macrophages which are not under negative feedback control.
therefore as more oxLDL is uptaken, more cytokines are released, more macrophages are recruited, more foam cells are made and the atheroschlerotic plaque grows postive feedback mechanism
these foam cells are apoptopic but if they arent removed by efferocytosis they can burst, releasing more cytokines and chemokines and the necrotic core can grow (secondary necrosis)
what are the main roles of the endothelial layer?
provides a barrier between blood and tissue layers
secretes anticlotting factors into the blood/regulate haemostasis
Sense changes in blood flow and shear stress using mechanoreceptors
Provide a non adherent luminal surface allowing smooth blood flow
describe the structure of a lipoprotein and explain why they are necessary in lipid transport
> > hydrophobic core, hydrophilic linig/evelope
The lipids to be transported are hydrophobic so require to be packed into a lipoprotein with a hydrophilic lining to be able to dissolve in the plasma
hydrophobic core of esterified cholesterol and TAG suitable for packing and storage
these hydrophobic TAGs are made via enterocytes or hepatocytes in the gut converting FFA to hydrophobic TAG
also surrounded by phospholipids (hydrophilic head) and free cholesterol as its partially hydrophobic (-OH) and apoplipoproteins needed for cell recognition.
Describe how nitric oxide regulates vascular tone
Draw a diagram
No is secreted by Endothelial cells as part of regulating vascular tone.
NO is synthesised from eNOsynthase using oxygen and arginine
When NO diffuses across the tunica intima and rwches VSMC it triggers signalling pathways that leads to relaxation of VSMC =vasodilation
(NO detected by NO sensitive guanylyl cyclase csstlasyses GMP to cGMP activating cGKI
How does nitric oxide create an antheroprotective environment
NO is secreted by Endothelial cells to regulate vascular tone and enables vasodilation to occur which would increase shear stress
To synthesise it, oxygen is required
Therefore NO will reduce the oxygen in the environment and reduce oxidation so the liklihood of oxidised LDL is reduced
During laminar flow, the expression of eNOS is actually increased! !
Can you name some mechanoreceptors of the endothelial cell. What do they do?
They can sense changes in shear stress and stretch and blood flow
> cillia cells, ion channels that are stretch sensitive
> adherin junctions recognise stretch between cells
> focal adheren junctions on basal side of membrane that connect to the ECM
Upon Recognition they can remodel the cytoskeleton and alter gene expression
Which is a true statement
A reduced expression of tight junctions is atheroprotective
B turbulent flow has increase risk of clotting
C expression of MCP1, NFkB and Il-8 increased in laminar flow
D increased expression of thrombodulin is proanthrogenic
OPTION B IS TRUE
Low tight junction expression means membrane more permeable so more Likely for LDL to reach intima
These are all chemokines/cytokines which promote inflammation
Thrombodulin is an Anticoagulant so that would be decreased in a proanthrogenic condition
what is ACAT?
it is enzyme = acylCoA cholesterol acyltransferase which esterifies cholesterol
cholesterol esters can then be stored in the cytoplasm as fat droplet
ACAT gene can be upregulated if there is excess cholesterol to prevent ER stress but this can only happen in a negative feedback mechanism
what actually casues endothelial cell disfuctnion?
turbulant flow and low shear stress can increase the permeability of endothelial cells and reduce expression of tight junctions so LDL can infiltrate into the t.intima
also endothelial cells express LOX-1 receptors bind to oxLDL which can promote disfunction even further as it has it can upregulate expression of these receptrs even more!
why would PDGF be increased in AS
PDGF encourages the differentiation of monocytes to phagocytitic macrophages to exressing scavenger receptors
Which are involved in the uncontrolled uptake of oxLDL
why is oxLDL not taken up by LDL receptor
oxidation can modify the apop100 protein meaning LDLr no longer recognises it
also scavenger receptors of macrophages have much higher AFFININTY for oxLDL
describe how a foam cell forms. how can this lead to a lipid necrotic core of AS?
macrophage will express scavenger receptors to uptake oxLDL
will then degrade it in lysosome and release free cholsetrol which is then reesteriied into a lipid drople
but then there is positive feedback and unregulated uptake of oxLDL so many fat droplets accumulate in macrophages = foam cells. high cholestrol = ER stress and leads to apoptosis or necrosis
there is normally efferocytosis occuring encouring remaval of these foam cells but this can be overwhelmed
can then burst releasing fat contents, contribution to necrotic core and release cytokines and chemokines too and drives chronic inflammation
how is a macrophage recruited to site of inflammation
so monocyte recruited by MCP1 and other chemokine expression
it will adhere to endothelial cells and transmigrate to t.intima by following a chemotaxis gradient
will differentiatate to macrophage encouraged by PDGF
how can AS inflammation be resolved
- phagocytrs secrete antiinfallamtory cytokines
- process of efferocytosis where the apoptopic foam cells express EAT ME LIGANDS on the surface encouring phagocytes to engulf and degrade them - very tightly controlled proces
BUT THIS CAN GO AWRY if there is an excess in foam cells
what are some VSMC markers.
(contractile protein specific)
MHC11 and SMC -actin and calponin which help to regualte VSMC contraction
what triggers VSMC to go to a synthetic phenotype
during an inflammatory response, VSMC will supress expression of contractile proteins
no longer be quiescent and will respond to GF to proliferate and migrate!!
will increase MMP expression to degrade the ECM and cell to cell adhesions
name some typical charactersitics of VSMC contractile phenotype?
quiescent so will not progress to G1/not proliferate as they have a low synthetic (synthesis) rate
non migratory
are VSMC good in AS?
yes - they migrate to the intima, proliferate and secrete collagen rich fibrous cap to stabilize necrotic core and prevent from bursting STABLE PLAQUE
no - around 50% foam cells are VSMC derived as they also express lox-1 and scavenger receptor
and these foam cells are very bad at efferocytosis
also become osteoblast like cells as they are exposed to cytokines that drive differentiation so promote calcifcation of the necrotic core
outline the different types of AS plaque
stable plaque - thick and fibrous and collagen rich
vunerable plaque - macrophage and foam cell rich
healed plaque - clinically silent but lumen size gets smaller and smaller
at what point do we see clinical symptoms of AS
once lumen is 70% occuled there is much reduction in bloodflow -> ischmia of tissue
stable or untable angina??
why is ApopE defient mice a good model of AS?
ApoplipoE is present on VLDL, HDL, IDL and its a high affinity ligand for liver-receptors enabling cholesterol export
it allows reverse cholesterol transport as the remmnants can be taken up by liver and excess cholesterol can be excreted as bile
so a KO will increase plasma levels of cholesterol so more likely for AS plaque to form as they are unable to be degreaded
> don’t need to feed a high fat diet either for mice model
how do statins help to treat AS?(main function)
inhibit action of HMG coA reductase so are actually the rate limiting step to cholestrol synthesis
as 80% cholestrol is made in the liver, use of statins will decrease amount of cholestrol and LDL significantly
> secondary effect is more LDL is taken up by cells via LDLr reducing plasma LDL even more!
how do statins help to treat AS? (additonal functions)
TEMPO
can decease thrombogenesis by decreasing platelet aggration
can upregulate expression of eNOS -> atheroprotective effect
can reduce MMP expression preventing VSMC phenotype switch
can reduce expression of proinflame cytokines, decreasing immune recruitment
describe the main differeence between a stable and vunerable plaque
stable - high number of sVSMC, thick fibrous cap, rich in collagen
low number of macrophages and foam cells
macrocalcification and some MMP expresssion to help VSMC migrate
vunerable - low number of sVSMC, thin fibrous cap, low in collagen
high number of INFLAMmacrophages and foam cells so cytokine release
microcalcification can disrupt the fibrous cap and high MMP expresssion to degrade the ECM
> prone to erosion or complete rupture
which matrix metalloproteases are implicated in formtion of vunerable plaque
MMP1 and MMP-8 which are increased in response to pro-inflame
MMP help to degrade the ECM making plaque unstable and more prone to rupture
also a reduction in TIMP which is inhibitor of MMP expression in the matrix furthur increasing collagen breakdown of ECM
describe what happens to the AS plaque upon rupturing?
once the necrotic core contents is exposed to blood it will initiate the wound healing process
> exposed collagen is paticualrly thrombogenic
this involves platelet aggregation and coagulation cascade but this OCCULUDES lumen and slows blood flow or break off and form an emboli
OR the thrombus can heal and form a HEALED plaque
what is angina? what is difference between stable and unstable angina
pain across chest due to reduced blood flow within coronary arteries
stable associated with a stable fibrous plaque and there will be pain during exercise/SNS stimulation but it is TEMPORARY
unstable angina associated with vunerable plaque and experience pain at all times even when resting
thrombosis can lead to Myocardial infarction and necrosis of myocardial tissue
why do we not know much about how a thrombus forms?
because mice models of AS do not rupture and form a thrombus
and complex lesions don’t form in the coronary arteries of the mice (they do in the aortic arch and carotid arteries) so hard to study CAD
human tissue sections are hard to get
