atherogenesis Flashcards
what are the stages of atherogenesis
normal fatty streak fibrous plaque occlusive atherosclerotic plaque plaque rupture Early stages clinically silent, increases with age
where do plaques develop
atherogenic plaques develop in tunica intima in artery wall
Caused by migration of cells from tunica media
Also caused by recruitment of leucoccytes and deposition of lipid from the blood
what makes up plaques
1 cells (SM cells, macrophages (foam cells), T cells) 2 matrix components (collagen, proteoglycans, elastic fibres) 3 intracellular and extracellular lipid (cholesterol and cholesterol esters)
what does a healthy endothelium do
Production of NO controls vasorelaxation and has anti-adhesive properties
what is the role of endothelium in atherogenesis
Normal endothelium has anti-coagulant and anti-adhesion properties
Early dysfunction/damage of the endothelium is functional rather than structural
Loss of cell-repellent quality
Allows inflammatory cells into vascular walls
Increased permeability to lipoproteins
Structural damage caused by processes above and is observed later in atherogenic process
what are the roles of monocytes in atherogenesis
Attracted to developing plaques by MCP-1/CCL2
Transform into macrophages under influence of cytokines (IFN-Y, TNF-a, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells
Generate reactive oxygen species (ROS) which oxidise LDL in intima
Produce pro-inflammatory cytokines
Express scavenger receptors
how are lipids involved in atherogenesis
Smaller lipoproteins (remnants and LDL) enter vascular wall more easily than other particles, hence more atherogenic Entry of lipoproteins into vascular wall occurs more easilt when present in high concentrations in the blood Lipoproteins in vascular wall can be oxidised in the intima (by oxidases and ROS from macrophages and ROS from VSMCs)
what do oxidised LDLs do
Stimulates expression of VCAM-1 and MCOP-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 fatty streaks)
how do macrophages become foam cells
oxidised LDL not recognised by LDL receptor but by scavenger receptor
accumulation of lipids in the form of cholesterol esters in the cytosol
receptors controlling cholesterol exported down regulated
what is VSMC migration
endothelial dysfunction
Endothelial cells and macrophages secrete PDGF and TGF-B
Effect – proliferation and migration into the intima
Can differentiate into macrophages like cells and become foam cells
Activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque
Migrating cells and deposits of ECM material all disrupt the structure of the arterial wall
what are types of atherosclerotic plaque
stable (lipid pool and thick fibrous cap, preserved lumen, high VSMC content) or vulnerable (necrotic core, thin fibrous cap, thrombosis of ruptured plaque, VSMC content)
what are the two major theories as to the cause of atherogenesis
lipid oxidation hypothesis
response to injury hypothesis
what is the lipid oxidation hypothesis
LDL enters vascular wall + oxidised Oxidised LDL phagocytksed by macrophages generation of foam cells recruitment of macrophages generation of plaques
what is the response to injury hypothesis
endothelial injury/dysfunction accumulation of lipoproteins vessel wall monocyte adhesion platelet adhesion smooth buckle proliferation lipid accumulation - plaques
what is familial hypercholesterolaemia
Genetic disorders – 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
