Atherosclerosis Flashcards
What is atherosclerosis?
A progressive disease involving the thickening of artery wall due to the accumulation of fatty material leading to the production of an atheromatous plaque.
Fatty/fibrosis tissue accumulate in the intima of arteries/arterioles.
Over time the plaque develops a fibrotic cap and accumulates calcified material.
Advanced plaques can disrupt blood flow by reducing lumen size and cause ischaemia.
Atheromatous lesion could be disrupted and lead to thrombosis - ischaemia.
Where do atheromatous plaques develop?
What diseases are related to these plaques?
IN medium-large sized blood vessels, particularly:
Right carotid artery = Carotid artery disease.
proximal left anterior descending coronary artery = coronary heart disease.
Left renal artery = Chronic kidney disease.
What are risk factors of atherogenesis?
Diabetes, smoking, gender, age, genetic conditions (familial hypercholesteremia, Tangier’s disease)….
Dyslipoproteinemia.
What are the general differences between LDL’s and HDL’s?
elevated LDL is a risk factor for atherosclerosis and are characterised by Apolipoprotein B100 (ApoB100).
HDL’s are considered protective, with reverse transport of cholesterol to the liver.
HDL’s have igher ptotein content and contain Apolipoprotein A1 (ApoA1)
How are lipids transported from the gut around the body?
Niemann pick C1 like protein is expressed in intestinal epithelial cells is essential for cholesterol absorption.
Cholesterol and FA’s are combined Apolipoprotein B100 into chylomicrons.
Chylomicrons are circulated and encounter Lipoprotein lipase (LPL) expressed on vascular endothelial cells.
LPL breaks down chylomicron to form chylomicron remnants (CMR).
CMR’s are absorbed into the liver by LRP1…
In the liver, HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis/mevallonate pathway and converts HMG-CoA to mevalonic acid.
In the liver, cholesterol, triglycerides and Apolipoprotein B100 are packaged to form VLDL.
LPL on vascular endothelial cells removes FA’s from VLDL’s to form LDLs.
LDL’s are taken up into the liver or by peripheral cells via LDL receptors.
ABC transporters transport cholesterol from cells where it combines with ApoA1, to form HDL’s..
HDL’s are reuptaken into the liver by SRB1.
What are the initial steps of atherosclerosis?
Endothelial cell dysfunction:
Reduced bioavailability of NO.
Upregulation of adehsion receptors.
Increased endothelial permeability to LDL.
What is the CANTOS study?
Cannakinumab is a monclonal antibody that targets IL-1b.
It was a randomised RCT for people with previous MI and high levels of C-reactive protein, suggesting a high inflammatory profile.
Cannakinumab had a significant effect in reducing serious CV events.
= It didn’t cholesterol, only inflammation!!!
= Proving that inflammation was such an important part of athersclerosis, not just cholesterol!
Cholesterol crystals activate NLRP3 inflammasome in macrophages - which generates Il-1b from pro Il-1b.
How does endothelial dysfunction lead to athersclerosis?
Upregulation of adhesion receptors, increased LDL permeability, and reduced NO bioavailability.
More LDL permeates into the subendothelial/intima layer.
BUT LDL is retained because ApoB100 binds to negatively charged ECM proteoglycans.
Retained LDL’s are susceptible to oxidation by ROS or enzymes like lipoxygenases.
= Forming oxLDL/Oxidised LDL.
Why do immune cells acumulate in the intima layer?
Endothelial cells overexpress VCAM-1 and other adhesion receptors which increase the recruitment and adhesion of monocytes, and enhance diapedesis of monocytes.
Monocytes in the intima differentiate into macrophages due to M-CSF in intima.
What is the role of immune cells in atherosclerosis?
Increased monocyte invasion of intima and differentiation into macrophages by M-CSF.
Macrophages produce pro-inflammatory mediators, ROS and TF = Tissue factor amplifies pro-coagulants, starting the clotting cascade.
= promoting local inflammation, more recruitment of immune cells, and thrombosis.
Differentiated macrophages can engulf ox-LDL to form Foam Cells.
How do macrophages form Foam Cells?
Macrophages engulf ox-LDL in the intima layer.
Class B scavenger receptor (CD38), and SR-A…. are upregulated in macrophages.
Scavenger receptors bind + internalise ox-LDL - driving Foam Cell formation…
ACAT1 conerts cholesterol into cholesteryl esters which form lipid droplets in the macrophage….
Equally, ABCA1 can efflux cholesterol, which can combine with ApoA1, to form HDL…
How do cholesterol crystals form?
In macrophages/Foam Cells, free cholesterol can crystallise to form cholesterol crystals.
Cholesterol crystals are highly inflammatory and amplify the pro-inflammatory response.
Cholesterol crystals develop early on in atherogenesis, and correspond with increase in IL-1b concentrations.
As Cholesterol crystals activate NLRP3 inflammasome, which produces IL-1b, from pro IL-1b.
What happens to Foam Cells?
Foam cells release inflammatory cytokines which enhance inflammatory response.
But When Foam cells become overwhelmed, they undergo apoptosis and necrosis.
= Leading to the accumulation of extracellular cholesterol and debris in the intima.
What is the NLRP3 inflammasome?
The NLRP3 inflammasome cleaves proIL-1b into active IL-1b.
Cholesterol crystals activate the NLRP3 inflammasome, which produces more IL-1b.
What are the end stages of atherscleorsis?
As the lesion develops, from the apoptosis and necrosis of foam cells and release of cholesterol crystals, there is a build up of lipid/cholesterol rich necrotic core.
Tunica media smooth muscle cells start to migrate into the intima, and can become Foam cells too!
But smooth muscle cells accumulate under the endothelial layer, and are rich in collagen.
Fibrosis cap forms from collagen exposure to blood and tunica media SM cells. Collagen within the fibrosis cap triggers platelet activation and TF expression, leading to clot formation.
