Atherogenesis and diet Flashcards
Atherogenesis progressive process
Normal-> Fatty streak -> Fibrous plaque -> Occlusive atherosclerotic plaque -> Plaque rupture
Atherogenic plaques
- cells (smooth muscle cells, macrophages (foam cells), T cells)
- matrix components (collagen, proteoglycans, elastic fibres)
- intracellular and extracellular lipid (cholesterol and cholesterol esters)
Role of the endothelium
Normal endothelium has anti-coagulant and anti-adhesion properties
Early dysfunction/ damage of endothelium is functional rather than structural
- loss of cell-repellent quality
- allows inflammatory cells into vascular wall
- increased permeability to lipoproteins
Structural damage
Caused by processes above and is observed later in atherogenic process
Role of monocytes
Attracted to developing plaques by MCP-1/ CCL2
Transform into macrophages under influence of cyotkines secreted by endothelium and vascular smooth muscle cells
Generate ROS which oxidise LDL in intima
Produce pro-inflammatory cytokines
Express scavenger receptors
Cytokines which influence monocytes macrophages
IFN-gamma
TNF-alpha
GM-CSF
M-CSF
Lipid involvement in atherogenesis
Smaller lipoproteins enter vascular wall more easily than other particles so more atherogenic
Can be oxidised in the intima
Oxidised LDL
Stimulates expression of VCAM-1 and MCP-1; directs macrophages to sites of lesions
Oxidised B-100 binds to scavenger receptors on macrophages and is phagocytosed
Ned feedback regulation via cholesterol concentration
Generation of foam cells
Migration of VSMC
Responsible for structure of vessel wall
Endotherlial cells and macrophages secrete: PDGF and TGF beta
Effects on VSMCs: proliferation and migration into the intima
Activated VSMCs also synthesise ECM which deposits in the plaque
Summary of atherogenesis
- Endothelial dysfunction/ injury/ and/ or entry of LDL into intima of artery where it is oxidised
- Damaged endothelium causes monocytes to adhere and enter artery wall
- Monocytes differentiate into macrophages and phagocytose oxidised LDL via scavenger receptors to become foam cells
- Foam cells produce inflammatory molecules sustain the inflammatory response and recruit more monocytes and damage the endothelium further
- Foam cells and VSMCs build up in the intima, producing collagen all of which disrupt the structure of the vessel wall
Stable plaque
Thick fibrous cap/ high collagen content
High VSMC content
Small lipid pool
Few inflammatory cells
Ruptured plaque
Thin fibrous cap/ low collagen content
Low VSMC content
Large lipid pool
Many inflammatory cells
VSMC
Vascular smooth muscle cell
2 theories of what causes atherogenesis
Lipid oxidation hypothesis
Response to injury hypothesis
Lipid oxidation hypothesis
LDL enters vascular wall and becomes oxidises
Oxidised LDL phagocytised by macrophages
Generation of foam cells
Recruitment of macrophages
Generation of plaques
Response to injury hypothesis
Endothelial injury. dysfunction
Accumulation of lipoproteins in vessel wall
Monocyte adhesion
Platelet adhesion
Smooth muscle proliferation
Lipid accumulation- plaques
Hypothesis 1: endothelial injury due to
Raised LDL
‘Toxins’ e.g. cigarette smoke
Hypertension
Haemodynamic stress
Hypothesis 2: endothelial injury caused by
Platelet adhesion, PDGF release, VSMC proliferation and migration
Insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
Migration of monocytes into intima
Atheroma- a unifying hypothesis 3
Stimulated VSMC produce matrix material
Foam cells secrete cytokines causing:
- further VSMC stimulation
- recruitment of other inflammatory cells
