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Abstract
During atherosclerosis, the gradual accumulation of lipids into the subendothelial
space of damaged arteries results in several lipid modification processes followed
by macrophage uptake in the arterial wall. The way in which these modified lipoproteins
are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived
macrophage and thus its transformation into the foam cell that makes up the characteristic
fatty streak observed in the early stages of atherosclerosis. The unique expression
of chemokine receptors and cellular adhesion molecules expressed on the cell surface
of monocytes points to a particular extravasation route that they can take to gain
entry into atherosclerotic site, in order to undergo differentiation into the phagocytic
macrophage. Indeed several GWAS and animal studies have identified key genes and proteins
required for monocyte recruitment as well cholesterol handling involving lipid uptake,
cholesterol esterification and cholesterol efflux. A re-examination of the previously
accepted paradigm of macrophage foam cell origin has been called into question by
recent studies demonstrating shared expression of scavenger receptors, cholesterol
transporters and pro-inflammatory cytokine release by alternative cell types present
in the neointima, namely; endothelial cells, vascular smooth muscle cells and stem/progenitor
cells. Thus, therapeutic targets aimed at a more heterogeneous foam cell population
with shared functions, such as enhanced protease activity, and signalling pathways,
mediated by non-coding RNA molecules, may provide greater therapeutic outcome in patients.
Finally, studies targeting each aspect of foam cell formation and death using both
genetic knock down and pharmacological inhibition have provided researchers with a
clearer understanding of the cellular processes at play, as well as helped researchers
to identify key molecular targets, which may hold significant therapeutic potential
in the future.