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Biochem basis of human disease > atherosclerosis > Flashcards

atherosclerosis Flashcards

1
Q

what is the middle of an artery called

A

lumen

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2
Q

the artery is made of three layers. these are:

A

tunica intima
tunica media
adventitia

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3
Q

what does atherosclerosis cause

A

hardening of the arteries

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4
Q

atherosclerosis is the principle cause of heart attack, strokes and gangrene of the extremeties T/F

A

T

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5
Q

when does atherosclerosis cause the most problems

A

plaque ruptures leading to thrombus formation

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6
Q

what does atherosclerosis always begin with

A

an insult to the artery wall (damage to endothelial cells)

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7
Q

which risk factors of athersclerosis cause endothelial cell dysfunction

A

dyslipidaemia
diabetes (type 2)
smoking

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8
Q

what is the biggest risk factor of atherosclerosis

A

age

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9
Q

where are atherosclerotic plaques found

A

within the peripheral and coronary arteries

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10
Q

what is the distribution of atherosclerotic plaques governed by

A

haemodynamic factors

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11
Q

which areas are prone to atherosclerosis

A

bifurcations - one artery branching into 2 or bending

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12
Q

an atherosclerotic plaque is a complex lesion consisting of what (4)

A

lipid
necrotic core
connective tissue
fibrous cap

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13
Q

eventually an atherosclerotic plawue will occlude (block) the vessel lumen this results in

A

restriction in blood flow (angina)

or rupture of blood vessel

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14
Q

the healthy endothelium produces …. and other mediators to protect against atherosclerosis

A

NO

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15
Q

when there is endothelial dysfunction this alters NO biosynthesis which predisposes to atherosclerosis T/F

A

T

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16
Q

when there is damaged endothelial cells what are released and a concentration gradient produced

A

chemoattractants

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17
Q

what do damaged endothelial cells also express

A

adhesion molecules

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18
Q

what are the steps to the adhesion cascade

A
  1. damaged endothelial cells express adhesion molecules such as selectins
  2. neutrophils are captured by selectins which cause them to slow doen and roll along vessel wall
  3. leukocytes express integrins. these bind adhesion molecules on endothelial cells
  4. stimulates retraction of endothelial cells so neutrophils can move into tissue by chemotaxis
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19
Q

what is another stimulus of atherosclerosis

A

LDL

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20
Q

how is LDL a stimulus of atherosclerosis

A

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

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21
Q

intermediate lesions in the progression of atherosclerosis are composed of layers of what

A
  • foam cells
  • vascular smooth muscle cells
  • T lymphocytes
  • adhesion and aggregatin of platelets to vessel wall
  • isolated pools of extracellular lipids
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22
Q

what is reverse cholesterol transport

A

pathway for plaque reduction involving HDL

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23
Q

HDL contains …. particles that interact with foam cells to collect cholesterol. mature HDL then travels to liver to release cholesterol

A

apo-A1

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24
Q

for progression of atherosclerosis and formation fo fibrous plaques or advanced regions you need an added impetus eg

A

another risk factor or an area of disturbed flow

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25
Q

dense fibrous cap overlies

A

lipid rich core

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26
Q

cap is made of

A

extracellular matrix proteins

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27
Q

lipid core is made of

A

necrotic and apoptotic debris, smooth muscle cells, foam cells, macrophages and T lymphocytes

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28
Q

fibrous cap has to be reabsorbed and redeposited in order to be maintained T/F

A

T

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29
Q

large numbers of macrophages predispose plaques to rupture. How?

A

increase matrix metalloproteins (degrade cap) so cap becomes weak

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30
Q

plaque rupture provides a substrate for what

A

thrombus formation and vessel occulus

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31
Q

plaque rupture/erosion is induced by what

A

cholesterol crystallisation

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32
Q

the different forms of lipoproteins are classified according to what?

A

density and the alipoprotein they express

33
Q

which is the biggest of the lipoproteins

A

chylomicron

34
Q

what alipoproteins do all lipoproteins express when they are matured

A

ApoC and ApoE

35
Q

alongside ApoE and ApoC, what other alipoprotein does chylomicrons express

A

ApoB48

36
Q

alongside ApoE and ApoC, what other alipoprotein does LDL, IDL and VLDL express

A

ApoB100

37
Q

alongside ApoE and ApoC, what other alipoproteins does HDL express

A

ApoA1 and ApoA2

38
Q

lipoproteins transport themselves around the body in 3 pathways. these are

A
  • exogenous
  • endogenous
  • reverse cholesterol
39
Q

what happens in the exogenous pathway

A
  • 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
40
Q

in exogneous pathway how is the cholesterol transported out of small intestine lumen into lymph vessel

A

via protein NPCL1L1

41
Q

in exogenous pathway what donated ApoE and ApoC to the chylomicron

A

HDL

42
Q

what does the chylomicron need to be active

A

ApoE and ApoC

43
Q

what activates lipoprotein lipase which breaks down the chylomicron to release cholesterol and triglycerides

A

ApoC

44
Q

after cholesterol is released in exogenous pathway what happens to it and the chylomicron

A

cholesterol can be taken up by tissues

remnants of chylomicron are taken up by liver where it binds by specific receptors

45
Q

where does the endogenous pathway start

A

at the liver (where cholesterol is made)

46
Q

what are the steps to the endogenous pathway

A
  • 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
47
Q

when VLDL is hydrolysed by lipoprotein lipase what is it converted into

A

intermediate LDL (ILDL)

48
Q

intermediate LDL circles around body until it reaches another tissue where it can be hydrolysed. what does it become when its hydrolysed

A

LDL

49
Q

HDL has ApoA1 which reacts with ABC-A1 and ABC-G1 in macrophages/foam cells to adsorb ….into HDL

A

cholesterol

50
Q

after cholesterol is adsorbed into HDL from macrophages/foam cells, how is the cholesterol transported to the liver

A

indirect pathway or direct pathway

51
Q

in the indirect pathway, cholesterol is transferred to VLDL and LDL via what

A

cholesterol ester transport protein (CEPT)

52
Q

after cholesterol is transferred to VLDL and LDL particles via CEPT, how does the cholesterol in the LDL get to liver

A

LDL binds LDLR on liver

53
Q

how does cholesterol reach the liver via the direct pathway

A

ApoA1 of HDL binds SRB1 receptor on the liver. choelsterol transferred to liver. HDL recirculates

54
Q

what happens to cholesterol in the liver

A

processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion

55
Q

do the 3 pathways interact

A

yes

56
Q

what is dyslipidaemia

A

abnormal amount of lipid in the blood

57
Q

what is dyslipidaemia primarily due to

A

combination of diet and genetics

58
Q

what gives a greater risk of dyslipidaemia

A

type II: familial hypercholesterolaemia

59
Q

what is the secondary cause of dyslipidaemia

A

consequence of other conditions eg diabetes, alcoholism, chronic renal failure

60
Q

what is familial hypercholesterolaemia

A

genetic disorder causing high levels of LDL in blood and early cardiovascular disease

61
Q

most familial hypercholesterolaemia mutations are in which 2 genes

A

LDLR gene

ApoB

62
Q

what do the main treatments of atherosclerosis/dyslipidaemia aim to do

A

decrease the levels of LDL

63
Q

what are the 3 main types of drugs available for dyslipidaemia/atherosclerosis

A

statins
inhibitors of cholesterol absorption
PCSK9 inhibitor

64
Q

what do statins target

A

cholesterol synthesis

65
Q

what is the main regulatory step in cholesterol synthesis

A

conversion of HMG-CoA to mevalonate catalysed by HMG-CoA reductase

66
Q

what do statins inhibit

A

HMG-CoA reductase - enzyme in the main regulatory step of cholesterol synthesis

67
Q

what is the mechanism of action of statins

A

reduced cholesterol synthesis in liver causes increase LDL receptor synthesis

  • increased LDL clearance into liver
  • therefore statins reduce plasma LDL
68
Q

by inhibiting the mevalonate pathway, statins affect lipidation. how?

A

products of the mevalonate pathway are involved with lipidation

69
Q

what is an example of an inhibitor of cholesterol absorption

A

Ezetimibe

70
Q

how does ezetimibe work

A

blocks intenstinal absorption of cholesterol by blocking a transport protein (NPC1L1)

71
Q

what are another example of cholesterol absorption inhibitors

A

sterols/stanols

72
Q

how are sterols/stanols inhibitors of cholesterol absorption

A

structurally similar to cholesterol - incorporated into mixed micelles replacing cholesterol

73
Q

what may sterol/stanols also activate which increases movement f cholesterol from enterocyte back into the intestinal lumen to be secreted

A

ABCG5/G8

74
Q

why do plant stanols retain their effect long term

A

virtually unabsorbed by the body

75
Q

what is PCSK9

A

a negative regulator of low density lipoprotein receptor (LDLR)
binds to LDLR so LDL continues to circulate

76
Q

what is an example of a PCSK9 inibitor

A

repatha (evolocumab)

77
Q

how does repatha work

A

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

78
Q

what does repatha do

A

increased number of LDLRs available to clear LDL from blood

lowers circulating LDL levels

79
Q

imbalance of lipid transport leads to dyslipidaemia which can lead to

A

atherosclerosis

Biochem basis of human disease (6 decks)

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