Lectures 16 and 17 Atherosclerosis Flashcards
When is inflammation good?
fighting against pathogens, parasites, tumours
wound healing
When is inflammation bad?
myocardial reperfusion injury atherosclerosis IHD rheumatoid arthritis asthma inflammatory bowel disease shock excessive wound healing restenosis
What is modern day clinical problem with inflammation?
availability of antibiotics and advance trauma surgical techniques make the magnitude of inflammatory response a bigger treat than infection or injury
Define Atherosclerosis
chronic inflammatory disease influenced by many factors involving a vast array of inflammatory cells and cytokines
describe the pathogenesis of atherosclerosis
influenced by lifestyle and medical choices
influenced by the haemodynamics of the blood
can begin before birth and take years or decades to develop
symptoms often indicate advanced state of disease
beings with initial insult to artery wall
What are the non-modifiable risk factors of atherosclerosis?
age gender - male genetics inflammation family history of CV disease
What are the modifiable risk factors of atherosclerosis?
dyslipidaemia diabetes hypertension obesity smoking/alcohol stress physical activity
Where are atherosclerotic plaques most likely to form?
peripheral and coronary arteries - at bifurcations
distribution impacted by haemodynamic factors
What is the mechanism that initiates atherosclerosis?
endothelial dysfunction
altered NO biosynthesis
accumulation of inflammatory cells
Give examples of atherosclerotic stimuli
How do they lead to atherosclerosis?
adhesion - chemoattractants - transmigration of leukocytes oxidised LDL (oxLDL) - engulfment by macrophages forming foam cells which release more pro-inflammatory cytokines
What cytokines are found in atherosclerotic plaques?
IL-1, IL-6, IL-8 IFN-gamma TGF-beta MCP-1 PDGF
What is the process of atherosclerosis progression?
stage 1 - endothelial dysfunction, accumulation of lipid-laden macrophages with migrate into the vessel all (chemotaxis) and form foam cells (LDL engulfed) forming fatty streaks in the intimal layer - appear from 10 years old
stage 2 - intermediate lesions - foam cells and T-lymphocytes. VSMC migration into intima. platelet adhesion and aggregation to vessel wall. lipid transport in balance - LDL delivery and HDL removing cholesterol
stage 3 - added impetus needed - fibrous cap (collagen and elastin) with lipid core containing necrotic and apoptotic debris, SMCs, foam cells and macrophages
stage 4 - thinning of the cap, MMPs, weakening cap prone to rupture. may impeded blood flow.
What is the function of the reverse cholesterol transport pathway?
How does the reverse cholesterol transport work?
removes cholesterol from peripheral tissues and returns it to the liver
HDL contains apo-A1 particles that interact with ABC-A1 or ABC-G1 transport proteins in foam cells (macrophages) to adsorb cholesterol
mature HDL travels to liver to release cholesterol which is processes for excretion - indirectly or directly
HDL continues to recirculate
What is the difference between a ruptured and eroded plaque?
ruptured - thin fibrous cap, collagen-poor fibrous cap, large lipid core, many macrophages and fibrin-rich thrombus
eroded - proteoglycan and glycosaminoglycan rich, little-or-no lipid core, neutrophils and NETs, many smooth muscle cells and platelet-rich thrombus
What is the structure of lipoproteins?
central core of hydrophobic lipid - triglycerides and cholesterol
surrounded by hydrophilic coat - phospholipids, free cholesterol and apolipoproteins
What are the different classifications of lipoproteins?
What are the diameters of each lipoprotein class?
chylomicros - 100-1000nm
very-low density lipoprotein (VLDL) - 30-100nm
low density lipoprotein (LDL) - 20-30nm
high density lipoprotein (HDL) - 7-20nm
What apolipoproteins do each class of lipoproteins contain?
chylomicros - apoB-48
VLDL - apoB-100
LDL - apoB100
HDL - apoA1 and apoA2
What are the three lipoprotein transport pathways?
exogenous (dietary)
endogenous
reverse cholesterol
Describe the exogenous lipoprotein pathway
lipids are digested
chylomicrons assembled with apoB-48 and move into the liver then subsequently into the bloodstream
HDL donates apoC-II and apoE to form mature chylomicrons which activate lipoprotein lipase (LPL)
LPL catalyses a hydrolysis reaction releasing glycerol and fatty acids which can be absorbed by the tissue
remnants endocytosed and hydrolysed by lysosomes
chylomicron remnants taken up into the liver - cholesterol is stored and secreted into bile which can be oxidised into bile acids or converted into VLDL
What is the function of ApoC?
only bind to receptors found on adipose tissue
What is the function of ApoE?
only bind to receptors on hepatocytes
What is the endogenous lipoprotein pathway?
in liver - triglycerides and glycerol assembled with apoB-100 to form VLDL
HDL donates apoC-II and apo-E
apoC-II activates LPL causing hydrolysis of VLDL releasing glycerol and fatty acids which can be absorbed by adipose tissue and muscle
hydrolysed VLDL now called IDLs can be taken up into the liver, hydrolyses by hepatic lipase into LDL, or remain in circulation
IDLs return to the liver and are hydrolysed by hepatic lipase releasing glycerol and triglycerides leaving behind LDL
What is the indirect HDL cholesterol transport pathway?
cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport protein (CETP)
LDL binds to LDLR on the liver
What is the direct HDL cholesterol transport pathway?
Apo-A1 of HDL binds SRB1 receptor on liver
cholesterol transferred to liver
HDL recirculates
Define Dyslipidaemia
abnormal amount of lipid in the blood
What is primary dyslipidaemia?
cause - combination of diet and genetics
usually polygenic but can be monogenic