Atherosclerosis ad lipoprotein metabolism Flashcards
Recall the 8 summary steps of atherosclerotic plaque production
- LDL infiltration
- Monocyte infiltration –> macrophage (M)
- LDL engulfed by M –> foam cell
- Foam cell evacuated
- Ms overwhelmed by LDL
- Lipid core formation
- Inflammation + fibrous thickening
- Collagen production by VSMCs
Recall the role of macrophages in atherosclerosis
- Foam cell formation
2. Release GFs that stimulate VSMCs to produce collagen
Recall the mechanism of foam cell production from LDL
LDL bound to endothelium by proteoglycans
LDL oxidised by free radicals
Phagocytosed by Ms –> foam cell
Recall 4 families of molecules secreted by activated macrophages
Cytokines for monocyte recruitment
GF for VSMCs
Proteinases for fibrous cap
TF to stimulate coagulation cascade
What is the effect of Cholesteryl-ester transport protein and reverse cholesterol transport?
HDL –> LDL
What is the first line of treatment for dyslipidaemia?
Statins
Recall the mechanism of action of statins
Act on mevalonate pathway by inhibiting HMG-CoA reductase - reducing production of 2 key molecules:
1. Geranyl pyrophosphate
2. Farnesyl pyrophosphate
Reduced cholesterol production
How does decrease in cholesterol production improve lipid profile
Less cholesterol synthesised –> LDL receptors upregulated in response –> bind to circulating LDLs –> plasma LDL reduced
What is the most common statin available?
Rosuvastatin
Describe the dose-response phenomenon observed in statin therapy
Initial dose gives a good reduction in LDL, but doubling the dose only gives a further 6% reduction in LDL
What is the function of geranyl and farnesyl pyrophosphatase
Small lipids that are extremely important in protein modification and activation
What is a possible use for statins outside of dyslipidaemia treatment?
Have an inflammatory effect in the CVS and systemic inflammatory processes - may be used for arthritis/ IBD?
Other than statins, recall 5 possible lines of therapy for dyslipidaemia
(For no extra cholesterol production) Fibrates Nicotinic acid Exetimibe CETP and RCT Anti-PCSK9
What is the function of fibrate drugs?
TG-lowering - more effective than statins at this fx
HDL level increases (most important effect)
What is the mechanism of action of fibrates?
PPAR-alpha receptor agonists
What does “PPAR receptor” stand for?
Peroxisome-proliferator-activated receptors
What is nicotinic action used for?
Increasing HDL
Summarise the benefits and disadvantages of nicotinic acid treatment
Benefit: effective at lowering pretty much every parameter of CVS risk
Disadvantage: not really used in practice as side effect profile so massive
What is the main use of exetimibe?
When used in addition to statin can lower the LDL level significantly, rather than having to doulble statin dose for just 6% beneficial change
What is the mechanism of action of exetimibe?
Inhibits cholesterol absorption
What is the function of anti-PCSK9?
PCSK9 inhibits LDL receptor, so drug protects receptor to allow it to work effectively
