atherogenesis Flashcards
where in the artery do plaques develop?
- atherogenic plaques develop in the tunica intima of the artery wall
- caused by migration of cells from the tunica media
- also caused by recruitment of leucocytes and deposition of lipid from the blood
what are the 3 components that make up atherogenic plaques?
1) cells (smooth muscle cells, macrophages, T cells)
2) matrix components (collagen, proteoglycans, elastic fibres)
3) intracellular and extracellular lipid (cholesterol and cholesterol esters)
what causes a healthy endothelium?
production of nitric oxide control vasorelaxation and has anti-adhesive properties
what is the role of endothelium in atherogenesis?
- normal endothelium has anti-coagulant and anti-adhesion properties
what does early dysfunction/damage of the endothelium lead to?
- it is functional rather than structural
- loss of cell-repellent quality
- allows inflammatory cells into vascular wall
- increased permeability to lipoproteins
what are the roles of monocytes in atherogenesis?
- attracted to developing plaques by MCP-1/CLL2
- transform into macrophages under influence of cytokines secreted by endothelium and vascular smooth muscle cells
- generate reactive oxygen species (ROS) which can oxidise LDL in intima
- produce pro-inflammatory cytokines
- express scavenger receptors
how are lipids involved in atherogenesis?
- smaller lipoproteins enter vascular wall more easily than other particles; hence more atherogenic
- entry of lipoproteins into the vascular wall occurs more easily when present in high concentrations in the blood
- lipoproteins in the vascular wall can be oxidised in the intima
what is the role/function of oxidised LDL?
- stimulates expression of VCAM-1 and MCP-1; directs monocytes to sites of lesions
- oxidised B-100 binds to scavenger receptors on macrophages and is phagocytosed
- no feedback regulation via cholesterol concentration
- generation of foam cells (visible in arterial walls as fast streaks)
what happens with the migration of VSMC?
- VSMCs are responsible for structure of the vessel wall
- endothelial cells and macrophages secreted PDGF and TGF-beta
- effect on VSMCs: proliferation and migration into the intima
- VSCMs can differentiate into macrophage-like cells and become foam cells
- activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque
- migrating cells and deposited of ECM material all disrupt the structure of the arterial wall
what are the characteristics of stable plaque?
- thick fibrous cap/high collagen content
- high VSMC content
- small lipid pool
- few inflammatory cells
what are the characteristics of ruptured plaque?
- thin fibrous cap/low collagen content
- low VSMC content
- large lipid pool
- many inflammatory cells
what is the lipid oxidation hypothesis?
1) LDL enters vascular wall and becomes oxidised
2) oxidised LDL phagocytised by macrophages
3) generation of foam cells
4) recruitment of macrophages
5) generation of plaques
what is the response to injury hypothesis?
1) endothelial injury/dysfunction
2) accumulation of lipoproteins in vessel wall
3) monocyte adhesion
4) platelet adhesion
5) smooth muscle proliferation
6) lipid accumulation - plaques
what is familial hypercholesterolaemia (FH)?
- genetic disorder: autosomal inheritance in genes related to LDL metabolism resulting in lifelong elevation of LDL-C levels
- if untreated many patients with FH die of myocardial infarction or other major CV events
how do you prevent atherogenesis?
- protection of artery walls (stop smoking, lower blood pressure)
- reduce plasma lipid levels
- reduce ROS and inflammation
