Atherosclerosis II Flashcards
pathogenesis: endothelial cell dysfunction
-does not require denudation, localized to intima
-enhanced by agents toxic to endothelial cells (smoking,
homocysteine, diabetes)
-increased in areas of high turbulence and pressures (bifurcations, ostia)
components of atherosclerosis
- endothelial cell dysfunction
- increased vascular permeability
- increased binding of platelets, monocytes
- accumulation of lipids
pathogenesis: increased binding of platelets, monocytes
- activation of endothelial cells
- platelets, monocytes roll and adhere as they do in inflammation
- expression of adhesion molecules by activated endothelial cells, platelets, and monocytes results in adhesion and migration (monocytes which become macrophages)
pathogenesis: accumulation of lipids
-both intracellular (early) and extracellular (late)
deposition
accumulation of lipids
- “insudation” or direct deposition due to increased
vascular permeability - finish later
pathogenesis: oxidized lipids
-The most important receptor is not the LDL receptor, but
the scavenger receptor that binds oxidized lipids.
-oxidized lipids are also chemotactic for monocytes;
they decrease macrophage motility and increase
production of inflammatory cytokines
-oxidized lipids are also thought to be toxic to
endothelial cells and smooth muscle cells
key points of serum lipids
-7% of body’s cholesterol circulates as LDL
-IDL is the immediate precursor to LDL
-(VLDL is immediate precursor to IDL)
-HDL is NOT related to VLDL/IDL/LDL – has
different apoproteins
-LDL: Apo-protein B and E
-HDL: Apo-protein AI and AII
-HDL can scavenge excess cholesterol and is
protective
increased cholesterol levels
-suppress cholesterol synthesis;
induce esterification and storage of cholesterol;
and suppresses the synthesis of LDL receptors.
how is most LDL cleared
cleared by and metabolized in the liver via cell surface receptors
pathogenesis: activation of monocytes; secretion of cytokines
migration of monocytes into intima
-begin to accumulated lipid, resulting in foam cells
-insudation of lipid (particularly oxidized lipid) may by
chemotactic for monocytes
-secrete cytokines (IL-1/TNF) and other factors which
cause migration and proliferation of smooth muscle cells
(FGF, TGF-b; PGDF from platelets)
-toxic oxygen species from macrophages may result in
further oxidation of lipid species
pathogenesis: migration and proliferation of smooth muscle cells
-respond to production of cytokines by endothelial cells,
platelets, and macrophages in intima
-migrate from media into intima
-accumulate lipid and for foam cells
-secrete extracellular matrix, including collagen
-formation of fibrous cap over necrotic lipid center
pathogenesis: aging
Fibrotic plaque becomes unstable
-“fracture” of fibrous plaque results in exposure of collagen and adhesion of platelets
-thrombosis can cause acute occlusion of medium
sized arteries (coronary arteries, cerebral vessels)
-fracture can also lead to “rupture” with embolization of cholesterol
key components of pathology of atherosclerosis
- Fibrous cap
- Necrotic lipid center
- “Shoulders” with activated cells
- Foam cells
- Migrating and proliferating smooth muscle cells
pathology: organization
- all events in intima
- endothelium is usually intact
- fibrous cap is made up of modified smooth muscle cells and dense connective tissue (collagen)
- smooth muscle cells act as modified fibroblast like cells which proliferate and secrete ECM
- combination of fibrosis and calicification results in raised, white to yellow lesions
lipid accumulating in organization
both intracellularly and extracellularly
-yellow centers with lipid and necrotic debris are
described as “gumatous” (like gruel)
-BOTH macrophages and smooth muscle cells take up
oxidized LDL to form foam cells
-Necrotic center consists of foam cells, lipid, and debris
-Cholesterol deposition may result in formation of
cholesterol crystals
