Pathogenesis of Atherosclerosis Flashcards
development of atherosclerosis
chronic inflammatory response in the subintima of elastic and muscular arteries
accumulation of macrophage-derived “foam cells”
migration and proliferation of vascular smooth muscle cells
cellular buildup outgrows its supply of oxygen and nutrients at its center
resulting necrosis stimulates more inflammation and the lesion grows
mature lesions have a fibrow cap of caollagen and smooth muscle cells overlying a necrotic core of cellular debris
results of a ruptured atherosclerotic lesion
myocardial infarct
cerebral infarct
gangrene of extremities
abdominal aortic aneurysm
fatty streak
a subintimal accumulation of lipid-laden macrophages called foam cells
may progress into mature atherosclerotic lesions, but they often regress
mature atherosclerotic lesion
consists of a fibrous cap of proliferating vascular smooth muscle cells that produce collagen overlying a necrotic core of cellular debris
contents of the necrotic core
cell debris from macrophage- and later on in the progression of the lesion, smooth muscle cell-derived foam cells
free cholesterol can crystallize in this region as well
calcium is also present
contents of the fibrous cap
smooth muscle cells
macrophages
foam cells
lymphocytes
collagen
elastin
proteoglycans
How do atherosclarotic lesions grow and heal?
from the edges, so the oldest part of the lesion with the most advanced changes will be toward the center
more recent damage will be at the interface with the normal tissue
Why does atherosclerosis begin at branch points and ostea?
due to changes in laminar flow, which allows leukocytes to slow down
instead of being swept along with the current, leukocytes are being activated
complications of atherosclerosis
calcification
fissuring/ulceration/plaque hemorrhage
atheroembolism
aneurysm formation
atherosclerosis and chronic inflammation process
- Monocytes migrate into subintima in response to inflammatory stimuli
- T Lymphocytes migrate into subintima
- Release of cytokines and vascular smooth muscle cell (SMC) mitogens
- Recruitment of mesenchymal cells (SMC)
- Proliferation of mesenchymal cells (SMC)
- Production of extracellular matrix (collagen) by SMC
- Macrophages digest debris
- High levels of matrix metalloproteinases (at edges)
- Inflammatory cells secrete angiogenic factors
- Angiogenesis
- Attempts to restore healthy tissue
Why does cholesterol build up in atherosclerotic lesions when the LDL receptor and its regulation are not designed to accumulate it?
macrophage scavenger receptors recognize modified LDL (oxidized, aggregated, acylated) and are NOT down-regulated
scavenger receptors keep taking in cholesterol, even after it has accumulated to toxic levels
Describe the oxidized LDL control pathway.
LXRs suppress inflammation and and promote lipid efflux, preventing inflammation
foam cells
macrophages that have tried to clear the altered lipoproteins but took in too much and their catabolic activity got overwhelmed
if conditions continue unabated, they will die by apoptosis
the inability of newly-recruited macrophages to clear the apoptotic cells cause foam cells to die by secondary necorsis, forming the necrotic core
factors that promote atherosclerosis
LDL modification
infection
unknwon “endothelial cell dysfunction”
trauma
immunity (prevents atherosclerosis)
modifying enzymes from endothelial cells, macrophages, and smooth muscle cells involved in atherosclerosis
oxidases
proteases
sphingomyelinase
phospholipase A2
cholesterol esterase
toxic/proinflammatory products of LDL
oxidized lipids
aggregated LDL
ceramide
lysoPC
free cholesterol
experimental evidence for the role of innate and adaptive immunity in the pathogenesis of atherosclerosis
patients taking statins (which have anti-inflammatory effects as well as lipid-lowering effects) were
protected from atherosclerosis out of proportion to the degree of cholesterol and LDL reduction
SLE and genetic polymorphisms in TLR4 are associated with higher incidence of atherosclerosis
in mice, inflammation and immunity have been shown to be critical for the development of atherosclerosis, and interference with the inflammatory or immune process significantly blocks atherosclerosis despite continued high circulating cholesterol and LDL levels
C-reactive protein (CRP)
an acute phase protein released by the liver in response to acute systemic inflammation
elevated in people with coronary artery disease, 4x increased in people in MI
found in atherosclerotic lesions
binds LDL and allows uptake of unmodified LDL
activates endothelial cells and stimulates secretion of IL6 and MCP-1
additional risk factors for atherosclerosis
chlamidia pneumoniae and cytomegalovirus infections
circulation of endotoxin (LPS)
D299G polymorphism in TLR-4
systemic lupus erythematosus
op mutation
no monocytes/macrophages
smaller lesion size
MCP-1 mutation
no monocyte chemoattractant
smaller lesion size
CCR2 mutation
no MCP-1 receptor
smaller lesion size
VCAM-1 mutation
very low VCAM-1 levels
smaller lesion size
Tbet mutation
no helper T cells
smaller lesion size
