Atherosclerosis 3 Flashcards
What is lipoprotein (a)
Cholesterol rich LDL particle containing:
1 molecule of ApoB100 and Apolipoprotein a linked via disulfide bond…
Lipoprotein (a) is a risk factor for CVD:
Lipoprotein a accelerated atherogenesis = deposition of Lp(a) in intima.
Lp(a) has anti-fibrinolytic effects = structurally homologous to plasminogen, but no fibrinolytic activity …
What is the role of plasminogen?
Plasminogen is converted to plasmin by tPA.
Plasmin converts insoluble fibrin into soluble fibrin fragments.
Fibrinolytic = dissolves clots in atherosclerosis!
What is Tangiers disease?
A severe deficiency/absence of HDL with tissue accumulation of cholesterol esters.
Caused by mutations in ABCA1 transporter on Chromosome 9.
It is an autosomal recessive disorder.
What is the role of ABCA1?
ABCA1 transports an array of molecules including cholesterol out of cells.
Extracellular cholesterol can form cholesterol ester droplets which then combine with ApoA1, ApoA2 to form HDL for reverse cholesterol transport.
What are the symptoms of Tangiers disease?
Severe deficiency/absence of HDL.
Orange-yellow tonsils, enlarged lymphoid tissue, increased risk of atherosclerosis, hepatospenomegaly.
How does Tangiers disease lead to HDL effects?
severely deficient/absence of HDL.
ABCA1 mutations lead to loss of function in chromosome 9.
Autosomal recessive, so both parents.
Lack of export of cholesterol = build up of intracellular cholesterol, depleted extracellular cholesterol esters…
As there is v. little cholesterol ester droplets, ApoA1 does not combine with it, so is cleared from plasma.
What is familial hypercholesterolemia?
Severely elevated LDL cholesterol leading to atherosclerotic plaque formation in coronary arteries and proximal aorta at an EARLY age.
Most often leads to coronary artery disease = manifest as angina and myocardial infarction.
Most often from mutations in gene expression of LDL receptor
What are the symptoms of familial hypercholesterolemia?
Elevated LDL cholesterol.
Which becomes deposited in many tissues.
Cholesterol nodules called xanthomas can form in the skin, eyelids, tendons..
Arcus corneae before age of 45.
Cholesterol crystals deposit in synoval fluid in the joints.
What are the outcomes of homozygous FH and heterozygous FH?
Homozygous FH die of coronary artery disease in childhood!
Heterozygous have milder outcomes, which can vary…
What are the treatments of familial hypercholesterolemia?
Need to reduce LDL cholesterol!!!
Statins
Bile acid resins
Fibrates.
LDL apheresis = dialysis…
Liver transplants..
What are common models for atherosclerosis?
LDL receptor knockout mice!!
Elevates LDL, leads to atherosclerotic lesions…
with high fat western diet.
What are Genome wide association studies?
GWAS studies.
You look for genetic variants to see if they’re associated with a trait, like CAD.
PCSK9, LDL receptor, IL-6R…
What triggers thrombosis formation in atherosclerosis?
Fibrous cap forms over the lipid rich necrotic core containing collagen and SMC foam cells.
Apoptosis of overwhelmed Foam Cells leads to release of matrix metalloproteinases (MMPs) which can digest collagen + thin fibrous cap, making susceptible to rupture.
Rupture or superficial erosion can lead to exposure of collagen, triggering platelet adhesion (via vWF) and activation.
Endothelial cells expressing tissue factor will lead to activation of intrinsic clotting cascade.
Forming thrombosis.
What is the role of platelets in atherosclerosis?
Thrombin receptors and purinergic receptors (P2Y receptors).
Platelets express scavenger receptor (CD36) = recognising oxLDL.
release of pro-inflammatory signallers.
What do the different scavenger receptors mediate in different cells?
CD36 in macrophages mediates foam cell formation
Platelet CD36 mediates activation.
CD36 is a class B scavenger recetpro that binds oxLDL, collagen and thrombospondin.
