Atherosclerosis

Question 1

what is atherosclerosis?

Answer 1

accumulation of fatty/fibrosis tissue in the inner most layer of arteries (intima)

leads to thickening of artery wall and production of atheromatous plaque

Question 2

what happens to atheromatous plaque over time?

Answer 2

develops fibrotic cap and accumulates calcified material

disrupts blood flow by reducing size of lumen

leads to tissue schema (lack of oxygen)

Question 3

which type of lipid is a risk factor for atherosclerosis?

Answer 3

LDL

[HDL = protective for atherosclerosis]

Question 4

what type of protein is associated with LDL?

Answer 4

apolipoprotein B100

Question 5

what type of protein is associated with HDL?

Answer 5

apoliprotein A-1

Question 6

why cholesterol important?

Answer 6

for membrane, myelin sheath and hormone regeneration

Question 7

how does cholesterol get in the body via diet

Answer 7

TG-transfer protein adds proteins = chylomicron

Enters bloodstream and is broken down by lipoprotein lipase enzyme

releases fatty acids (taken up by adipocytes in body)

Question 8

what is the co-enzyme responsible for cholesterol synthesis? and what inhibits this?

Answer 8

HMG co-enzyme A reductase

statins

Question 9

lipoprotein accumulation

Answer 9

apoB100 binds to -vely charged extracellular matrix proteoglycans = retention of LDL

Question 10

immune cell accumulation

Answer 10

activated endothelial cells express adhesion proteins that recruit inflammatory cells

migrate into arterial wall

causes monocytes differentiate into macrophages

Question 11

diapedesis

Answer 11

attachment and migration of monocytes through endothelial layer

Question 12

what do monocyte derived macrophages produce?

Answer 12

pro-inflammatory mediators

reactive oxygen species

tissue factor

Question 13

which scavenger receptors are highly regulated in monocyte/macrophage differentiation?

Answer 13

class B (CD36)

SR-A

Question 14

what do scavenger receptors do?

Answer 14

bind and internalise oxidised LDL -> helping foam formation

Question 15

what does high expression of CD36 cause?

Answer 15

atherosclerotic lesions

Question 16

what happens to the free cholesterol molecules?

Answer 16

transported by ABCA1 and combine with apoA-1

then go back to liver

Question 17

what is formed when there’s an overwhelming amount of cholesterol in the body?

Answer 17

crystals

Question 18

NLRP3 inflammasome

Answer 18

activated by cholesterol crystals

cleaves proIL-1β into bioactive IL-1β

knocked out NLRP3 = protective

Question 19

what happens when the atherosclerotic lesion ruptures?

Answer 19

high levels of cholesterol in bloodstream

leads to platelet activation

Question 20

necrotic core of atherosclerotic lesion

Answer 20

accumulation of apoptotic cells, debris and cholesterol crystals

Question 21

how are lipids/cholesterol transported?

Answer 21

as lipoprotein complexes

Question 22

which protein is associated with VLDL?

Answer 22

apoB100

Question 23

which protein is associated with chylomicrons?

Answer 23

apoB-48

Question 24

exogenous pathway

Answer 24

[GI TRACT]

transported as chylomicrons in lymph then blood

metabolised by lipoprotein lipase

remnants transported to liver + bind to receptors

undergo endocytosis

Question 25

endogenous pathway

Answer 25

[LIVER]

packaged into VLDL particles

metabolised by lipoprotein/hepatic lipase into LDL

returns to plasma in HDL particles

Question 26

statins

Answer 26

HMG-CoA reductase inhibitors

reduce circulating LDL

Question 27

other actions of statins

Answer 27

improve endothelial function

reduce vascular inflammation

reduce platelet aggregation

increased neovasculation of ischemic tissue

Question 28

fibrates

Answer 28

agonists PPARα nuclear receptors

increase gene expression of lipoprotein lipase

= decreases plasma VLDL
= increases plasma HDL

Question 29

bile acid resins

Answer 29

anion exchange resins

causes increased clearance of LDL-cholesterol from circulation

Question 30

LDL and protein PCSK

Answer 30

bind and then degraded

if they don’t have this, they’re recycled back to membrane (cycle of taking up LDL)

Question 31

PCDK9

Answer 31

post-translationally regulates hepatic LDL receptors

binds + causes degradation

Question 32

PCDK9 inhibitors

Answer 32

blocks PCDK9

causes more cell surface hepatic LDL receptors

= decrease in plasma LDL levels

Question 33

Framingham Risk Score

Answer 33

estimation of 10-year CVD risk of a person

Question 34

lipoprotein A

Answer 34

cholesterol-rich LDL particle with 1 molecule of apoliprotein B100 and additional protein apolipoprotein (a)

attached via disulphide bond

= risk factor at increased levels

Question 35

Tangiers disease

Answer 35

genetic disorder

deficiency/absence of HDL

Question 36

Tangiers disease - symptoms

Answer 36

orange-yellow tonsils

enlarged lymphoid tissue

corneal opacities

Question 37

discovery of genetic background of Tangiers disease

Answer 37

mutations on chromosome 9q31+ ABCA1 transporter

abnormal lipid trafficking

Question 38

Familial hypercholesterolemia (FH)

Answer 38

severely elevated LDL at early age

Nodules of cholesterol “xanthoma” in skin, eyelids and tendons

Question 39

Familial hypercholesterolemia (FH) - homozygote

Answer 39

die of early coronary disease in childhood

Question 40

Familial hypercholesterolemia (FH) - heterozygote

Answer 40

1 in 500 have milder and variable clinical course

Question 41

Familial hypercholesterolemia (FH) - treatment

Answer 41

statins

liver transplant - severe cases

Question 42

CD36

Answer 42

= class B scavenger receptor that binds to oxidised LDL

macrophage CD36 - mediates foam cell formation

platelet CD36 - platelet activation

Question 43

macrophages main use

Answer 43

inflammation

engulf lipoproteins to form foam cells