Ageing is a major risk factor for cardiovascular disease as demonstrated by increased risk of atherosclerosis in the elderly. Chronic inflammation is also elevated with age and may contribute to atherosclerosis pathogenesis.
Monocytes play an important role in the pathogenesis of atherosclerosis by migrating into the neointima of coronary arteries, ingesting deposited lipid and either migrating out, thus maintaining the health of the artery, or differentiating into foam cells which catalyse formation of atherosclerotic plaques. We hypothesise that monocyte activation in the setting of chronic inflammation increases the atherogenic properties of these cells by promoting their differentiation in to foam cells.
Using a novel model of human atherosclerotic plaque formation we measured the ability of freshly isolated monocytes to migrate across TNF-activated primary human endothelial cells (HUVEC) into a collagen matrix and differentiate into foam cells in the absence of exogenous modified lipid. We show that monocytes from healthy, older individuals (>65, n=20) migrate into the gel at comparable rates to monocytes from younger (<45, n=20) individuals. However, they form foam cells to a greater extent (24.5% vs. 44.5%, p<0.001) and have impaired reverse transmigration (p<0.05). We compared the ability of individual monocyte subsets to form foam cells and show that inflammatory CD14++CD16+ monocytes, which are expanded in elderly individuals (p<0.05), have a greater ability to form foam cells (n=3). Cells were isolated from the collagen matrix and foam cells had higher levels of intracellular TNF (p<0.05), decreased expression of the anti-inflammatory integrin CD11b (p<0.05) and higher levels of ceramides compared to monocyte-derived macrophages.
We conclude that inflammation, elevated in the elderly, activates monocytes and increases their atherogenic potential. This may represent a mechanism of increased CV risk in these individuals.