atherosclerosis Flashcards
what is the middle of an artery called
lumen
the artery is made of three layers. these are:
tunica intima
tunica media
adventitia
what does atherosclerosis cause
hardening of the arteries
atherosclerosis is the principle cause of heart attack, strokes and gangrene of the extremeties T/F
T
when does atherosclerosis cause the most problems
plaque ruptures leading to thrombus formation
what does atherosclerosis always begin with
an insult to the artery wall (damage to endothelial cells)
which risk factors of athersclerosis cause endothelial cell dysfunction
dyslipidaemia
diabetes (type 2)
smoking
what is the biggest risk factor of atherosclerosis
age
where are atherosclerotic plaques found
within the peripheral and coronary arteries
what is the distribution of atherosclerotic plaques governed by
haemodynamic factors
which areas are prone to atherosclerosis
bifurcations - one artery branching into 2 or bending
an atherosclerotic plaque is a complex lesion consisting of what (4)
lipid
necrotic core
connective tissue
fibrous cap
eventually an atherosclerotic plawue will occlude (block) the vessel lumen this results in
restriction in blood flow (angina)
or rupture of blood vessel
the healthy endothelium produces …. and other mediators to protect against atherosclerosis
NO
when there is endothelial dysfunction this alters NO biosynthesis which predisposes to atherosclerosis T/F
T
when there is damaged endothelial cells what are released and a concentration gradient produced
chemoattractants
what do damaged endothelial cells also express
adhesion molecules
what are the steps to the adhesion cascade
- damaged endothelial cells express adhesion molecules such as selectins
- neutrophils are captured by selectins which cause them to slow doen and roll along vessel wall
- leukocytes express integrins. these bind adhesion molecules on endothelial cells
- stimulates retraction of endothelial cells so neutrophils can move into tissue by chemotaxis
what is another stimulus of atherosclerosis
LDL
how is LDL a stimulus of atherosclerosis
LDL is oxidised by free radicals
oxidised LDL is engulfed by macrophages to form foam cells
foam cells release more pro-inflammatory cytokines - more macroophages engulf more LDL causing formation of fatty streak
intermediate lesions in the progression of atherosclerosis are composed of layers of what
- foam cells
- vascular smooth muscle cells
- T lymphocytes
- adhesion and aggregatin of platelets to vessel wall
- isolated pools of extracellular lipids
what is reverse cholesterol transport
pathway for plaque reduction involving HDL
HDL contains …. particles that interact with foam cells to collect cholesterol. mature HDL then travels to liver to release cholesterol
apo-A1
for progression of atherosclerosis and formation fo fibrous plaques or advanced regions you need an added impetus eg
another risk factor or an area of disturbed flow
dense fibrous cap overlies
lipid rich core
cap is made of
extracellular matrix proteins
lipid core is made of
necrotic and apoptotic debris, smooth muscle cells, foam cells, macrophages and T lymphocytes
fibrous cap has to be reabsorbed and redeposited in order to be maintained T/F
T
large numbers of macrophages predispose plaques to rupture. How?
increase matrix metalloproteins (degrade cap) so cap becomes weak
plaque rupture provides a substrate for what
thrombus formation and vessel occulus
plaque rupture/erosion is induced by what
cholesterol crystallisation
the different forms of lipoproteins are classified according to what?
density and the alipoprotein they express
which is the biggest of the lipoproteins
chylomicron
what alipoproteins do all lipoproteins express when they are matured
ApoC and ApoE
alongside ApoE and ApoC, what other alipoprotein does chylomicrons express
ApoB48
alongside ApoE and ApoC, what other alipoprotein does LDL, IDL and VLDL express
ApoB100
alongside ApoE and ApoC, what other alipoproteins does HDL express
ApoA1 and ApoA2
lipoproteins transport themselves around the body in 3 pathways. these are
- exogenous
- endogenous
- reverse cholesterol
what happens in the exogenous pathway
- cholesterol transported out of small intestine lumen into lymph vessels by NPC1L1
- packaged into inactive chlyomicron (doesnt have ApoC or ApoE ye so cant interact with other tissues)
- ends up in bloodstream
- HDL donates ApoC and ApoE
- chylomicron interacts with artery wall
- lipoprotein lipase activated via apoC - breaks down chylomicron to release cholesterol and triglycerides
in exogneous pathway how is the cholesterol transported out of small intestine lumen into lymph vessel
via protein NPCL1L1
in exogenous pathway what donated ApoE and ApoC to the chylomicron
HDL
what does the chylomicron need to be active
ApoE and ApoC
what activates lipoprotein lipase which breaks down the chylomicron to release cholesterol and triglycerides
ApoC
after cholesterol is released in exogenous pathway what happens to it and the chylomicron
cholesterol can be taken up by tissues
remnants of chylomicron are taken up by liver where it binds by specific receptors
where does the endogenous pathway start
at the liver (where cholesterol is made)
what are the steps to the endogenous pathway
- cholesterol packaged into VLDL
- inactive VLDL enters bloodstream
- HDL donates ApoC and ApoE
- interacts via ApoC with lipoprotein lipase which hydrolyses VLDL releasing cholesterol that the tissues can use
- VLDL shrinks in size and becomes intermediate LDL (iLDL) which circles around body to another tissue where it can be hydrolysed
- converted to LDL
- LDL cirulates until it hits tissue and releases cholesterol
when VLDL is hydrolysed by lipoprotein lipase what is it converted into
intermediate LDL (ILDL)
intermediate LDL circles around body until it reaches another tissue where it can be hydrolysed. what does it become when its hydrolysed
LDL
HDL has ApoA1 which reacts with ABC-A1 and ABC-G1 in macrophages/foam cells to adsorb ….into HDL
cholesterol
after cholesterol is adsorbed into HDL from macrophages/foam cells, how is the cholesterol transported to the liver
indirect pathway or direct pathway
in the indirect pathway, cholesterol is transferred to VLDL and LDL via what
cholesterol ester transport protein (CEPT)
after cholesterol is transferred to VLDL and LDL particles via CEPT, how does the cholesterol in the LDL get to liver
LDL binds LDLR on liver
how does cholesterol reach the liver via the direct pathway
ApoA1 of HDL binds SRB1 receptor on the liver. choelsterol transferred to liver. HDL recirculates
what happens to cholesterol in the liver
processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion
do the 3 pathways interact
yes
what is dyslipidaemia
abnormal amount of lipid in the blood
what is dyslipidaemia primarily due to
combination of diet and genetics
what gives a greater risk of dyslipidaemia
type II: familial hypercholesterolaemia
what is the secondary cause of dyslipidaemia
consequence of other conditions eg diabetes, alcoholism, chronic renal failure
what is familial hypercholesterolaemia
genetic disorder causing high levels of LDL in blood and early cardiovascular disease
most familial hypercholesterolaemia mutations are in which 2 genes
LDLR gene
ApoB
what do the main treatments of atherosclerosis/dyslipidaemia aim to do
decrease the levels of LDL
what are the 3 main types of drugs available for dyslipidaemia/atherosclerosis
statins
inhibitors of cholesterol absorption
PCSK9 inhibitor
what do statins target
cholesterol synthesis
what is the main regulatory step in cholesterol synthesis
conversion of HMG-CoA to mevalonate catalysed by HMG-CoA reductase
what do statins inhibit
HMG-CoA reductase - enzyme in the main regulatory step of cholesterol synthesis
what is the mechanism of action of statins
reduced cholesterol synthesis in liver causes increase LDL receptor synthesis
- increased LDL clearance into liver
- therefore statins reduce plasma LDL
by inhibiting the mevalonate pathway, statins affect lipidation. how?
products of the mevalonate pathway are involved with lipidation
what is an example of an inhibitor of cholesterol absorption
Ezetimibe
how does ezetimibe work
blocks intenstinal absorption of cholesterol by blocking a transport protein (NPC1L1)
what are another example of cholesterol absorption inhibitors
sterols/stanols
how are sterols/stanols inhibitors of cholesterol absorption
structurally similar to cholesterol - incorporated into mixed micelles replacing cholesterol
what may sterol/stanols also activate which increases movement f cholesterol from enterocyte back into the intestinal lumen to be secreted
ABCG5/G8
why do plant stanols retain their effect long term
virtually unabsorbed by the body
what is PCSK9
a negative regulator of low density lipoprotein receptor (LDLR)
binds to LDLR so LDL continues to circulate
what is an example of a PCSK9 inibitor
repatha (evolocumab)
how does repatha work
binds to PCSK9 to prevent it from binding to LDLR
prevents LDLR degradation
LDL binds to LDLR, internalises, LDL released
LDLR recycles back to liver cell surface
what does repatha do
increased number of LDLRs available to clear LDL from blood
lowers circulating LDL levels
imbalance of lipid transport leads to dyslipidaemia which can lead to
atherosclerosis
