pathological process that underlies several important disease states including cerebrovascular disease (stroke) and coronary artery disease (CAD)
atherosclerosis
involves thickening and hardening of large & medium sized arteries
atherosclerosis
lesion formed by lipid-rich macrophages lining the walls of the artery
plaque
4 changes lesions undergo
1) endothelial injury
2) fatty streak
3) fibrotic plaque
4) complicated lesion
causes for endothelial injury
smoking
inactivity
obesity
hypertension
diabetes
elevated LDL
reduced HDL
what occurs during endothelial injury
platelets arrive -> monocytes follow -> monocytes differentiate into macrophages
2 cells involved during endothelial injury
platelets
macrophages
macrophages that have absorbed oxidized LDL
foam cells
lesions with foam cells are extremely common - true/false?
true
composed of lesions containing foam cells producing ROS and continue to promote damage and sustain an inflammatory response with fibroblasts moving inward
fatty streak
formed when fibroblasts migrate over a fatty streak and combine with collagen produced by proliferating smooth muscle cells
fibrous plaque
atheroma
atherosclerotic lesions
asymmetric thickenings of the intima (innermost layer of the artery)
distinct regions in which atheroma occur
foci
components of an atheroma
1) center core consisting of lipid droplets & foam cells
2) cap of smooth muscle cells
3) ECM enriched in collagen fibers
point of growth in the atheroma where inflammatory & immune cells infiltrate and are most abundant
shoulder
ruptured plaques
complicated plaques
formed once a plaque ruptures leading to platelet aggregation and initiation of the clotting cascade
thrombus
2 major causes of coronary thrombosis
1) plaque rupture
2) endothelial erosion
condition in which ruptures preferentially occur
when the cap is thin and partially destroyed
factors secreted by activated inflammatory cells at sites of plaque rupture
matrix metalloproteinases
break down ECM and weakens plaque cap
matrix metalloproteinases
2 causes of endothelial erosion by macrophages
1) induce endothelial cells to undergo apoptosis
2) secrete proteases which cut the endothelial cell free from its basement membrane moorings
protein found on chylomicrons & IDLs, but not LDLs
ApoE
protein that binds to liver cells and is essential for the uptake and catabolism of fats & cholesterol
ApoE
phenotype of ApoE-/- mouse
develops spontaneous atherosclerosis
phenotype of LDLR-/- mouse
developed hypercholesteremia/massive degree of atherosclerotic plaques when fed high fat diet
endothelial damage is associated with _____.
oxidized LDL
what LDL is primarily comprised of
cholesterol
where LDL in body comes from
diet
increases both with the eating of high fat meals and with the degree of obesity of the individual
oxLDL
cells that can oxidize lipids while using up anti-oxidant defenses
activated neutrophils
type of LDL taken up by LDLR
MM-LDL
response by VECs to MM-LDL
secrete MCP-1 to attract monocytes
oxLDL receptor
CD36
phenotype of ApoE-/- CD36-/- cross
do not develop atherosclerosis
components of oxLDL that bind CD36
oxPCCD36
phosphatidyl choline derivative
first cells to arrive at the site of endothelial activation
platelets
important even in disease pathogenesis
adhesion of platelets
predictor of a future cardiac event in human patients with cardiovascular disease
platelet reactivity (spontaneous aggregation)
3 steps platelets undergo during the clotting process
1) adhesion
2) activation
3) aggregation
3 agonists platelet activation can be mediated by
1) TXA2
2) serotonin
3) ADP
change in platelets when they are activated
become spiky to create greater surface area to aggregate
how platelets are activated
activated platelets release agonist mediators
component of serum that promotes platelet activation
oxPCCD36 of oxLDL
the ability of platelets to aggregate and bind fibrinogen
platelet activation
factor that can induce platelets to activate
platelet agonist
CD36-/- people were (more/less) likely to develop atherosclerosis
more
-> unlike mouse data
M-CSF
macrophage colony stimulating factor
promotes differentiation of monocytes into macrophages
macrophages upregulate ____
TLR
can activate TLR
oxLDL
activated macrophages upregulate this process, resulting in large amounts of LDL entering the cell
pinocytosis
receptors (other than CD36) that can take up oxLDL
scavenger receptors
response by macrophages when large amounts of cholesterol are taken in
efflux by ABC transporters
MMP
matrix metalloproteinases
secreted by highly activated macrophage-derived foam cells
source of necrotic core found in atherosclerotic plaques