Lecture 16: Atherogenesis Flashcards
what is the first sign of atherogenesis visible without magnification?
Fatty streaks
Where do atherogenic plaques develop?
In the tunica intima
What causes atherogenic plaques to build up int he tunica intima?
The migration of cells from the tunica media and the recruitment of leukocytes from the blood
What are the three main components of an atherogenic plaque?
1: cells (smooth muscle cells, macrophages (foam cells), T cells)
2: matrix components (collagen, proteoglycans, elastic fibres)
3: intracellular and extracellular lipid (cholesterol and cholesterol esters)
What is produced by the endothelium to cause vasorelaxation?
NO
What are the effects of NO on the blood vessel?
Vasorelaxation, anti-adhesion, prevents platelet activation and neutrophil recruitment
Is the early dysfunction of the endothelium structural or functional?
Functional
What attracts monocytes to the developing plaques?
MCP1
What causes monocytes to transform into macrophages?
Cytokines (IFN-gamma, TNF-alpha, GM-CSF, M-CSF) secreted by the endothelium and vascular smooth muscle cells
What oxidises LDL in the intima?
Reactive oxygen species (ROS) from macrophages and VSMCs
What are the pro-inflammatory cytokines produced by monocytes/macrophages?
IL1, Il6 and TNFa
What type of receptors are expressed on the surface of monocytes/macrophages?
Scavenger receptors
Oxidised LDL stimulates the expression of what to direct macrophages to the sites of lesions?
VCAM1 and MCP1
What bind the scavenger receptors on macrophages?
Oxidised B-100 (it is then phagocytosed)
What happens to the receptors controlling cholesterol export when LDL is recognised by scavenger receptors rather than the LDL receptors?
They are down regulated
What type of cells secrete PDGF and TGF-b?
Endothelial cells and macrophages
What is the effect of secretion of PDGF and TGF-b?
Proliferation of VSMCs and their migration into the intima
Which cells synthesise ECM?
VSMCs
Which cells become foam cells?
Macrophages and VSMCs
What are the key features of a vulnerable plaque?
Thin fibrous cap
Large lipid pool
Many inflammatory cells
Low VSMC content
What are the key features of a stable plaque?
Thick fibrous plaque
Small lipid pool
Few inflammatory cells
High VSMC content
What is the definition of familial hypercholesterolaemia?
Genetic disorder of genes related to LDL metabolism resulting in lifelong elevation of LDL-C
What may cause endothelial injury?
Raised LDL
‘Toxins’ eg cigarette smoke
Hypertension
Haemodynamic stress
What is caused by endothelial injury?
Platelet adhesion, PDGF release, migration of monocytes into intima
Insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
VSMC proliferation and migration
Name a natural statin.
Lovastatin (mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor).
Name a synthetic statin.
Atorvastatin (Lipitor), Fluvastatin (Lescol)