Definition
chronic inflammatory disease of inner layer (tunica intima) of arteries, causing narrowing and hardening of arteries due to accumulation of lipid garbage (atheroma) followed by fibrosis
Definition (brief)
- chronic inflammation
- narrowing and hardening of arteries
- due to accumulation of lipid garbage (atheroma)
- fibrosis
chronic inflammatory disease of…?
tunica intima of arteries
most common cause of death in U.S.
atherosclerotic cardiovascular disease
Where does atherosclerosis occur?
medium (muscular) arteries --coronary --cerebral large elastic arteries --aorta
Favors branchpoints
pathogenesis
Response-to-injury hypothesis
- injury…
- accumulation…
- recruitment…
- foam cell formation…
- ECM deposition…
injury to endothelial cells by…
hemodynamic stress CO hyperglycemia hypercholesterolemia Chlamydia cytomegalovirus other factors
step one of response-to-injury hypothesis
injury to endothelial cells
- -causes impairment to permeability barrier
- -release of inflammatory cytokines
- -increased adhesion of monocytes
- -decreased secretion of vasodilators NO and prostacyclin
- -decreased release of antithrombotic substances
Step two of response-to-injury hypothesis
accumulation of lipid (esp. LDL) in tunica intima
- -LDL trapped by binding to ECM proteoglycans (whose production in increased by HTN)
- -LDL modified by oxidation, glycation, etc.
- -modified LDL promotes leukocyte recruitment and foam cell formation
foam cells
macrophages overstuffed w/ lipid
how do macrophages become overstuffed with lipid?
take up modified LDL via scavenger receptors, which lack feedback mechanism of LDL receptors (which shut down when cell is full to normal capacity)
Step three of response-to-injury hypothesis
leukocyte recruitment into tunica intima
Recruitment of smooth muscle cells into tunica intima
–transform from contractile cells into phagocytic cells
How is leukocyte recruitment into tunica intima mediated?
by endothelial expression of:
- -leukocyte adhesion molecules (LAM)
- -monocyte chemotactic protein 1
- -interferon-inducible protein 10 and IL-8
How is recruitment of smooth muscle cells into tunica intima mediated?
PDGF
TNF-alpha
TGF-beta
IL-1
Step 4 of response-to-injury hypothesis
foam cell formation
- -starts transformation of monocytes into macrophages
- -followed by phagocytosis of modified LDL via scavenger receptors (evading negative feedback inhibition…–>foam cells)
Step 5 of response-to-injury hypothesis
ECM deposition due to smooth muscle cell production of ECM
What mediates ECM deposition due to smooth muscle production?
IL-1
TNF-alpha
TGF-beta
FGF
The laying down of collagen represents…
irreversible component of atherosclerosis
How is the 5 step process to atherosclerosis thought to begin?
endothelial cell injury
