Atherosclerosis ad lipoprotein metabolism

Question 1

Recall the 8 summary steps of atherosclerotic plaque production

Answer 1

1. LDL infiltration
2. Monocyte infiltration –> macrophage (M)
3. LDL engulfed by M –> foam cell
4. Foam cell evacuated
5. Ms overwhelmed by LDL
6. Lipid core formation
7. Inflammation + fibrous thickening
8. Collagen production by VSMCs

Question 2

Recall the role of macrophages in atherosclerosis

Answer 2

1. Foam cell formation

2. Release GFs that stimulate VSMCs to produce collagen

Question 3

Recall the mechanism of foam cell production from LDL

Answer 3

LDL bound to endothelium by proteoglycans
LDL oxidised by free radicals
Phagocytosed by Ms –> foam cell

Question 4

Recall 4 families of molecules secreted by activated macrophages

Answer 4

Cytokines for monocyte recruitment
GF for VSMCs
Proteinases for fibrous cap
TF to stimulate coagulation cascade

Question 5

What is the effect of Cholesteryl-ester transport protein and reverse cholesterol transport?

Answer 5

HDL –> LDL

Question 6

What is the first line of treatment for dyslipidaemia?

Answer 6

Statins

Question 7

Recall the mechanism of action of statins

Answer 7

Act on mevalonate pathway by inhibiting HMG-CoA reductase - reducing production of 2 key molecules:
1. Geranyl pyrophosphate
2. Farnesyl pyrophosphate
Reduced cholesterol production

Question 8

How does decrease in cholesterol production improve lipid profile

Answer 8

Less cholesterol synthesised –> LDL receptors upregulated in response –> bind to circulating LDLs –> plasma LDL reduced

Question 9

What is the most common statin available?

Answer 9

Rosuvastatin

Question 10

Describe the dose-response phenomenon observed in statin therapy

Answer 10

Initial dose gives a good reduction in LDL, but doubling the dose only gives a further 6% reduction in LDL

Question 11

What is the function of geranyl and farnesyl pyrophosphatase

Answer 11

Small lipids that are extremely important in protein modification and activation

Question 12

What is a possible use for statins outside of dyslipidaemia treatment?

Answer 12

Have an inflammatory effect in the CVS and systemic inflammatory processes - may be used for arthritis/ IBD?

Question 13

Other than statins, recall 5 possible lines of therapy for dyslipidaemia

Answer 13

(For no extra cholesterol production)
Fibrates
Nicotinic acid
Exetimibe
CETP and RCT
Anti-PCSK9

Question 14

What is the function of fibrate drugs?

Answer 14

TG-lowering - more effective than statins at this fx

HDL level increases (most important effect)

Question 15

What is the mechanism of action of fibrates?

Answer 15

PPAR-alpha receptor agonists

Question 16

What does “PPAR receptor” stand for?

Answer 16

Peroxisome-proliferator-activated receptors

Question 17

What is nicotinic action used for?

Answer 17

Increasing HDL

Question 18

Summarise the benefits and disadvantages of nicotinic acid treatment

Answer 18

Benefit: effective at lowering pretty much every parameter of CVS risk
Disadvantage: not really used in practice as side effect profile so massive

Question 19

What is the main use of exetimibe?

Answer 19

When used in addition to statin can lower the LDL level significantly, rather than having to doulble statin dose for just 6% beneficial change

Question 20

What is the mechanism of action of exetimibe?

Answer 20

Inhibits cholesterol absorption

Question 21

What is the function of anti-PCSK9?

Answer 21

PCSK9 inhibits LDL receptor, so drug protects receptor to allow it to work effectively