Atherosclerosis Flashcards
how do macrophages die?
Where do their residue go?
At some point they become overwhelmed by the toxic metabolites from Oxidised LDLs
when this happens they die via apoptosis leading to all the toxins and tissue factors going into lipid necrotic core ‘central death zone’
Where are you more likely to get plaques?
Why?
Arterial bends and bifurcation
Due to the disturbed rather than laminar blood flow
What is main inflammatory cells in atherosclerosis?
What are the main functions of the two types of this cell?
What Is the main cytokine?
Macrophages coming from blood monocytes
Inflammatory macrophages adapted to kill microorganisms
Non-inflammatory macrophages for homeostasis
Interleukin-1
What are the types of lipoproteins and what do they each do?
What is the problem with the 3rd type of lipoprotein?
LDL- synthesised in liver carries cholesterol from liver to rest of body including arteries
HDL-carries cholesterol from peripheral tissue back to liver
OxDL-chemical modification of LDL by free radicals HIGHLY INFLAMMATORY AND TOXIC
How does LDL become trapped in the subendothelium?
How is this trapped subendothelial LDL modified?
What do macrophages do OxLDL
What does this process form?
LDL breaks through endothelial barrier and becomes trapped by binding to sticky matrix carbohydrates
Activated macrophages attack it with free radicals
This makes oxidised LDL, which is phagocytosed by macrophages = foam cells and chronic inflammation
What is familial hyperlipidemia?
What does it cause?
Autosomal genetic disease causing high levels of cholesterol and poorly clear LDL from blood
Cause xanthoma, foam cells and early atherosclerosis
How do we reduce cholesterol? (Two drugs)
What are their mechanisms?
HMG-coA- stops enzyme from making more cholesterol and therefore inhibits negative feedback loop
PCSK9 inhibitors-stops PCSK9 from degrading LDL receptors on the liver- these receptors remove cholesterol from blood by clearing LDL (bad lipoprotein) and puts it into the liver to suppress cholesterol biosynthesis (via neg feedback loop)
What are macrophage scavenger receptors?
What are the two types and what do they each bind to?
Receptors used to internalise oxidised LDL to arteries
A receptor- CD204 binds to OxLDL and bacteria
B receptor-CD36 binds to OxLDL and malaria parasites
What 4 things happen when macrophages get activated?
What can activate them?
What needs to be tightly balanced when it comes to collagen?
1.Have oxidative enzymes which can modify LDL
2.Phagocyte OxLDL and become foam cells under endothelium
3.Express cytokines mediatores that activate IL-1 and express chemokines which recruit more monocytes (which become macrophages)
4.Express GF that activate VSMC (vascular smooth muscle cells) which will make collagen adding to the arterial stenosis under the endothelium
HOWEVER, not enough collagen (caused by activated macrophages) will also be bad as the atherosclerotic plaque to rupture = thrombosis/myocardial infarction
How does atherosclerosis present?
What are the two main factors of atherosclerosis?
Death of downstream tissue- brain and heart
Angina
Myocardial infarction
Loss of one side of body
Inflammation of vessels and fatty deposits
What transcription factor coordinates a lot of mechanisms in atherosclerosis?
What two molecules does it activate?
Nuclear Factor Kappa-B
Master regulator of inflammation
Activates scavenger receptors and cytokine receptors eg IL-1
