Flashcards in Atherosclerosis Deck (46):
What are 3 endothelial cell adhesion mcs?
What is a foam cell?
Macrophage rich in cholesterol and cholesterol esters
Which kinds of T cells play a role?
Inflammatory TH1 lymphocytes play a role in lesion initiation, progression and instabilty-plaque rupture. Express IL-12, INF-gamma and TNF alpha which perpetuates macrophage and T cell proliferation.
*Also inc MMPs that degrade matrix and cap, while reducing sm cell proliferation and formation of the cap
What is obligatory for lesion initiation and prog?
Macrophages and LDL
Are lymphocytes obligatory for lesion initiation and prog?
No, but they exert a net pro atherogenic effect under less atherogenic pressures
What is HDL's role in atherosclerosis?
-Antiinflammatory effects (dec in adhesion mcs)
-HDL enters sub-endo space and effluxes cholesterol from macrophages/foam cells and then returns to plasma and carries that cholesterol to the liver for excretion
-inhibits LDL ox
-Upregulates prostacyclin and NO in endothelium and suppresses thrombosis
What signals for the change in sm phenotype?
Intigrins, adhesion mcs and chemokines produced in early lesions signal to medial smooth muscle cells
What changes in phenotype do sm's have?
-Switch from contractile to synthetic
-Migrate into neointima
-Undergo limited proliferation
-Secrete lareg amt of matrix
-Secrete cytokines, chemokines, growth factors and inflammatory prostaglandins
-Migrate to subendo location at sites of greatest hemodynamic stress and form fibrous cap
-Synthetic sm cells express scavenger receptors that can take up ox lipids and form sub pop of non macrophage foam cells
What growth factors do synthetic sm cells secrete?
PDGF, FGF, angiotensin II
Can foam cells contribute to lesion growth?
Yes, secrete all the things macrophages sec
What happens within the intermediate atherosclerotic lesion?
-Neo-intimal calcification (can image this)
-Remodeling (compensatory expansion with lumen occlusion)
Are intermediate lesions symptomatic?
Usually sub-clinical and asymptomatic but are most common lesion to cause plaque rupture at shoulder regions (large hemodynamic stress and most inflamm content)
Are intermediate lesions reversible?
Yes, or at least decreasable. Lipid lowering and BP control reduce CV events leading to stabilization and regression of the plaque
Is rupture related to vessel stenosis?
List the properties of a vulnerable plaque
-Thin fibrous cap
-Lots of macrophages and T cells
-Large lipid pool
-High ox LDL content
-Thin shoulder region
-Greater neovasc (brings in inflamm cells)
-Low VSMC count (vasc sm)
What overlapping mechanisms contribute to plaque instability?
-Impaired endoth fxn
-Impaired plaque stabilization
How do advanced lesions occur?
They are clinically silent and continue to grow or they rupture without clinical presentation. Some complex lesions can be contained and absorbed into an expanding lesion
Stage 1 of atherosclerotic lesions
Stage 2 of atherosclerotic lesions
Foam cells in intima
Stage 3 of atherosclerotic lesions
Extracellular lipid appears (ie apoptotic macrophages release fat cells)
Stage 4 of atherosclerotic lesions
Core formation begins (can go straight to stage 6)
-also called atheroma lesion
Stage 5 of atherosclerotic lesions
Cap and core formed
-also called fibroatheroma lesion
Stage 6 of atherosclerotic lesions
What is a fatty streak?
-Intracellular lipid filled foam cells
-Response to injury/inflammation
-Secrete pro-inflammatory cytokines that amplify inflammatory response
Within which vessels do atherosclerotic plaques form?
Elastic arteries, large and medium sized arteries
What are the components of a plaque?
-Cells (SMCs, macrophages, leukocytes)
-ECM (collagen, elastic fibers PGs)
-Lipid (intracellular and free)
What are some consequences of plaque rupture?
-Hemorrhage into the plaque
-Superimposed thrombosis due to exposure of ECM
What is percutaneous coronary intervention (PCI)?
Stick a balloon in the stenosis, then a stent
What is an unwanted consequence of PCI?
Restenosis (smc activation and constrictive remodeling)
Why does restenosis occur?
-The ECM is exposed due to the stress of the PCI procedure leading to platelet activation, release of cytokines and GFs
-SMcs are activated and become synthetic to secrete ECM into the intima forming a neointima within 7 days of injury
-Vascular remodeling occurs (shrinkage of lumen)-->this is what the stent stops (vessel contracts, but stent does not stop SMCs from migrating in)
What does PDGF do?
Induces SMC migration
What secretes PDGF?
Platelets, endothelial cells, macrophages, SMCs in response to vessel wall injury
What does basic FGF do?
induces SMC proliferation
What releases basic FGF?
SMCs in response to stretch or crush injury (both of which occur with PCI)
What is bFGF antibody?
It blocks 80% of SMC proliferation
What does ang II do with atherosclerosis?
Induces SMC proliferation
What can you give to attenuate neointimal formation?
What does TGF-beta do in atherosclerosis?
ECM secretion which makes up most of the restenotic region
What secretes TGF beta?
SMCs, endothelial cells, and platelets following PTCA
What do we do to inhibit SMC proliferation after PCI?
Put drugs on the stent like rapamycin or paclitaxel that inhibits its proliferation
What do the stent drugs target?
They inhibit the cell cycle in some way
What is a dangerous complication of PCI and stents?
Late thrombosis and neointimal atherosclerosis because you mess with the endothelial cells that are req to heal the artery. This allows blood clots to form occur
Is restenosis predictable?
Yes, if it doesn't occur within 6 mo of procedure it prob won't
Name the actions of AT1 receptor
AT1 receptor is a receptor for angioII
-Inc ox stress
Name the actions of AT2 receptor
AT2 receptor is a receptor for angio II, less densely distributed in the body than AT1
-Reduction in inflammation
-Reduction in remodeling
-Inc NO release