Atherogenesis Flashcards
The 3 components of an atherogenic plaque
- Cells:
Foam cells
Smooth muscle cells
T cells - Matrix component:
Collagen
Proteoglycans
Elastic fibres - Intra/Extracellular lipid:
Cholesterol
Cholesterol esters
Early dysfunction/damage to endothelium
Normal endothelium is supposed to have anti-adhesive and anticoagulant features.
When damaged:
Loses cell repellent quality- attracts more inflammatory cells in vascular wall
Increases permeability to lipoproteins.
These functional damages leads to structural damages
Monocytes in atherogenesis
MCP-1 attracts monocytes to developing plaque.
Transformation in macrophages inside vascular wall via cytokines secreted by the endothelium and VSMCs
Macrophages:
ROS production which oxidises LDL
Production of pro-inflammatory cytokines
Expression of scavenger receptors.
Cytokines released that transform monocyte to macrophages
IFN-gamma
TNF-alpha
GM-CSF
M-CSF
All secreted by the endothelial cells and VSMCs
MCP-1
Chemokine that attracts monocytes to a site.
Produced by endothelial and smooth muscle cells
Oxidised LDL and atherogenesis
Oxidised LDL stimulates expression of adhesins VCAM-1 and chemokine MCP-1.
More macrophages are directed to site of lesion- damage in endothelium.
Oxidised ApoB-100 now binds to scavenger receptors on macrophages instead of LDL receptors.
Generates foam cells
Oxidised B-100
ApoB-100 on LDL usually binds to LDL receptors. This is regulated by cholesterol synthesis in the cell.
Cholesterol synthesis decreases once more LDL is taken in via LDL receptors.
But when B-100 is oxidised, it now binds to scavenger receptors on macrophages instead of LDL receptors.
Causes oxidised LDL to be phagocytosed without a feedback regulation,
This generates foam cells that can burst.
Macrophage to foam cells
- Oxidised B-100 on LDL recognised by Scavenger receptor A.
- Oxidised LDL is taken in via endocytosis.
- This process is not regulated as export of cholesterol is limited.
- Intracellular cholesterol accumulates to form foam cells.
Foam cells
Macrophages that have digested excess cholesterol.
Show abnormal functions that accelerates atherogenesis:
Secretion of pro-inflammatory cytokines
MHC Class II expression
Increase in lipid uptake.
Increase in ROS synthesis.
PDGF and TGF-beta
PDGF: platelet derived growth factor.
TGF-beta: Transforming growth factor
Secreted by endothelial cells and macrophages which stimulate the proliferation and migration of VSMCs.
Role of VSMCs in atherogenesis
PDGF and TGF-beta attract VSMCs to the site of lesion.
They synthesis ECM and deposit into the plaque- especially collagen type III
6 summary steps of atherogenesis
- Endothelial dysfunction/ injury allows LDL to enter the intima of arteries. LDL is oxidised by ROS.
- Damaged endothelial cells release chemokines to attract monocytes which adhere and enter artery wall.
- Monocytes become foam cells by differentiating into macrophage which digest oxidised LDL.
- Foam cells release proinflammatory molecules and growth factors which recruit VSMCs to intima of vessel wall.
- Foam cells and VSMCs build up in intima and release collagen- disrupts blood vessel wall structure..
Causes of endothelial injury
Hyperlipidaemia
Hypertension
Smoking
Toxins
Haemodynamic factors.
Stable vs vulnerable plaque
Stable:
Thick fibrous cap
Small lipid content
Preserved lumen
Vulnerable: More vulnerable to thrombosis
Thin fibrous cap
Large lipid deposits
Many inflammatory cells present.
Endothelial theory of atherogenesis
- Endothelial injury or dysfunction.
- Accumulation of lipoprotein in vessel walls.
- Monocytes and platelets adhere to vessel walls.
- Cytokines released which stimulate VSMCs proliferation.
- Lipid accumulates and forms plaque.
