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M103 T3 > M103 T3 L16 > Flashcards

M103 T3 L16 Flashcards

1
Q

Which part of the artery wall do plaques develop in?

A

tunica intima

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2
Q

What are atherogenic plaques caused by?

A

the migration of cells from the tunica media to the tunica intima
disrupt the artery wall

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3
Q

What three principle compenents are atherogenic plaques made up of?

A

Cells
Matrix components
Intracellular and extracellular lipid

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4
Q

What types of cells are atherogenic plaques made up of?

A

smooth muscle cells
macrophages (foam cells)
T cells

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5
Q

What types of matrix components are atherogenic plaques made up of? (PEC)

A

proteoglycans
elastic fibres
collagen

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6
Q

What types of intra & extracellular lipid components are atherogenic plaques made up of?

A

cholesterol

cholesterol esters

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7
Q

What is the effect of the production of NO in a healthy endothelium?

A

generates an anti-adhesive environment

media promoting relaxation and growth inhibition

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8
Q

What is a condition of an anti-adhesive environment in endothelium?

A

where the recruitment of monocytes and platelets is inhibited
they won’t adhere to the endothelium layer

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9
Q

Which two properties are associated with the normal endothelium?

A

anti-coagulant properties

anti-adhesion properties

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10
Q

What are the differences between a normal endothelium and one that has some sort of early damage?

A

no structural differences - even under a microscope would look the same
functional differences - would function in a different way

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11
Q

What are the functional differences in a damaged endothelium?

A

loses cell-repellant properties
allows inflammatory cells into the vascular wall
increased permeability to lipoproteins

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12
Q

What is the inflammatory cell type that plays a fundamental role in atherogenesis?

A

monocytes

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13
Q

What are the roles of monocytes in atherogenesis?

A

they transform into macrophages under influence of cytokines
they generate Reactive Oxygen Species (ROS)
they produce pro-inflammatory cytokines

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14
Q

What substances attract monocytes to developing plaques?

A

MCP-1/CCL2

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15
Q

What receptors are expressed by monocytes?

A

scavenger receptors

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16
Q

Which cytokines transform monocytes into macrophages? (Iffny, Tiffnya, GeM, Mia

A

IFN-γ
TNF-α
GM-CSF
M-CSF

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17
Q

Where are the cytokines that transform monocytes into macrophages secreted from?

A

endothelium

vascular smooth muscle cells (VSMC)

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18
Q

What is the effect of ROS on LDL?

A

they can oxidise LDL in intima

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19
Q

Why are smaller lipoproteins considered more atherogenic than other lipoproteins?

A

they can enter vascular wall more easily than other particles, due to their size

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20
Q

What are considered smaller lipoproteins?

A

LDL and remnants

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21
Q

What can happen when lipoproteins enter the vascular wall?

A

they can be oxidised in the intima

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22
Q

What is the difference between oxidised and normal LDL?

A

ox’ed stimulates expression of VCAM-1 and MCP-1, which direct monocytes to the lesion sites
it is recognised by the B-100 scavenger receptors on macrophages and is phagocytosed

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23
Q

Which receptor is oxidised LDL recognised by?

A

the B-100 / scavenger receptors on macrophages

not the normal LDL receptors

24
Q

What is the process by which macrophages turn into foam cells?

A

scavenger / B-100 receptors on the macrophage surface recognise oxidised LDL
it is phagocytosed and let it inside the macrophage cell
the oxidised LDL is stored as cholesterol esters in the cytosol that accumulate into lipid drops
AAR, there is a downregulation of the receptors controlling cholesterol export
this messes up the feedback regulation via cholesterol concentration
the macrophages constantly phagocytose the oxidised LDL
the lipids accumulate
turns into foam cell

25
Q

What is an important feature of foam cells?

A

they are pro-inflammatory

26
Q

What two substances are secreted by foam cells?

A

ROS

inflammatory cytokines

27
Q

What two substances are secreted by endothelial cells and macrophages?

A

platelet derived growth factor

transforming growth factor-beta

28
Q

What is the effect of cytokines on the vascular smooth muscle cells?

A

they drive proliferation and migration into the intima

29
Q

Which two type of cells can develop into foam cells?

A

vascular smooth muscle cells

macrophages

30
Q

What conditions / substances can cause endothelial dysfunction or injury? (HyHyHa, SmoTo)

A

(Hyperlinda, Hypertensa, Haemadyno, Smokeytoxay)

hyperlipidaemia
hypertension
haemodynamic factors
smoking
toxins
31
Q

What are the features of a stabilised atherosclerotic plaque?

A

has a very small lipid pool
has a very thick fibrous cap (will have a high collagen content)
few inflammatory cells
the contents of the plaque are very much sequestered in the wall of the artery
they don’t extrude into the lumen

32
Q

What are the two types of atherosclerotic plaques?

A

stabilised

vulnerable

33
Q

What are the features of a vulnerable atherosclerotic plaque?

A

has a very large lipid pool
has a very thin fibrous cap
has many inflammatory cells
is present in much more inflammatory environments

34
Q

What are the two major theories of the causes of atherogenesis?

A

lipid oxidation hypothesis - older theory

“response to injury” hypothesis - newer theory

35
Q

What is covered by the lipid oxidation hypothesis for the causes of atherogenesis?

A

LDL enters vascular wall, becomes oxidised, is phagocytosed by macrophages
foam cells are generated, macrophages are recruited
plaques generated

36
Q

What is covered by the “response to injury” hypothesis for the causes of atherogenesis?

A 
endothelial injury / dysfunction
accumulation of lipoproteins in vessel wall
monocyte then platelet adhesion
smooth muscle proliferation
lipid accumulation
plaques generated
37
Q

What is the initiating factor for atherogenesis according to the “response to injury” hypothesis?

A

endothelial injury / dysfunction

38
Q

What is familial hypercholesterolaemia caused by?

A

mutations in genes related to LDL metabolism

can make the LDL receptor defective and non-functional.

39
Q

What is the level of LDL-cholesterol in a normal patient?

A

2.1

40
Q

Genetically, what type of condition is familial hypercholesterolaemia?

A

autosomal dominant disease

41
Q

What are the two genetic types of familial hypercholesterolaemia and what are the respective levels of LDL-c?

A

heterozygous - 9.6

homozygous - 15.5

42
Q

What happens to the patient if familial hypercholesterolaemia is left untreated?

A

fatal from myocardial infarction or other major CV events (20s. 30s)

43
Q

What does the unifying hypothesis of atherogenesis state that endothelial injury could be caused by?

A

raised LDL
toxins
hypertension
haemodynamic stress

44
Q

What does the unifying hypothesis of atherogenesis state that endothelial injury might cause?

A

platelet adhesion, PDGF release, migration of monocytes into intima
insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
VSMC proliferation and migration

45
Q

What does stimulated VSMC produce?

A

matrix material

46
Q

How can atherogenesis be prevented?

A

action that protects artery walls (stop smoking, lower bp)
reducing plasma lipid levels
reducing ROS and inflammation

47
Q

What is used to treat atherogenesis?

A

statins

Anti-PCSK9 antibodies

48
Q

What action is undertaken by statins?

A

they act as competitive inhibitors (stop the activity) of HMG-CoA reductase

49
Q

What happens in the pathway for cholesterol biosynthesis?

A

(ace, HMG, -ase, mev, squa and chol)

```
acetyl-CoA (C2
HMG-CoA
HMG-CoA reductase)
mevalonate (C6)
squalene (C30)
cholesterol (C27)
~~~

50
Q

How do statins block the action of HMG-CoA reductase?

A

they are bulky and literally get “stuck” in the active site
prevents the enzyme from binding with its substrate, HMG-CoA
no conversion of HMG-CoA to mevalonate

51
Q

What are the two classes of statins?

A

Natural

Synthetic

52
Q

What are examples of natural statins? (CLiPS)

A

Compactin
Lovastatin (mevacor)
Pravastatin (pravachol)
Simvastatin (Zocor)

53
Q

What are examples of synthetic statins?

A

(Ator Flu)
Atorvastatin (Lipitor)
Fluvastatin (Lescol)

54
Q

How do statins lower blood cholesterol?

A

the statin binds to enzyme HMG-CoA reductase
it inhibits this enzyme activity so cholesterol synthesis stops
the drop in intercellular cholesterol levels causes the cell to activate the SREBP-2 transcription factor

55
Q

What three things does SREBP-1 ics?

A

the expression of HMG-CoA reductase
the number of LDL receptors on the cell (how statins lower blood cholesterol)
the expression of PCSK9 (degrades LDL receptors for homeostasis)

56
Q

When are anti-PCSK9 antibodies used to treat atherogenesis?

A

in patients who can’t tolerate statins

in patients who can’t achieve sufficient blood lipid lowering with statins alone

57
Q

How do anti-PCSK9 antibodies work?

A

they block PCSK9 from binding to the LDL receptor
so it reduces the degradation of the LDL receptor
it leads to increased LDL receptor recycling into the membrane and greater uptake of LDL from the plasma

M103 T3 (21 decks)

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