Abstract 155: Contribution of Foamy Monocytes to Nascent Atherosclerosis

Infiltration of monocytes into the arterial wall and subsequent differentiation into macrophages, which take up lipoproteins to become foam cells, is a key step in atherogenesis. We reported that apoE -/- mice on high fat diet (HFD) for 12 weeks had foamy monocytes, characterized as intracellular lipid droplets, in blood. However, atherosclerosis starts early in apoE -/- mice after HFD, and it is unknown when foamy monocytes first appear in blood of apoE-/-mice after HFD and whether foamy monocytes contribute to nascent atherosclerosis. In the current study, apoE -/- and wild-type (WT) mice were fed HFD or normal diet (ND) for 1-5 weeks. Monocyte numbers increased in apoE -/- mice from 1 week on HFD. Importantly, foamy monocytes began appearing in blood of apoE -/- mice within 1 week on HFD. The proportion of foamy to total monocytes increased from ~20% at 1 week to ~40% at 5 weeks on HFD. The majority (~85%) of foamy monocytes were CD11c + while the majority of nonfoamy monocytes were CD11c - in apoE -/- mice on HFD. Foamy monocytes also expressed higher levels of TNF-α and scavenger receptors including CD36 and CD204 than nonfoamy monocytes. Cholesteryl-ester-rich VLDL were isolated from apoE -/- mice on HFD, labeled with DiI and intravenously injected into apoE-/- mice on ND (recipients). At 3 hours post injection, both CD11c + and CD11c - monocytes in recipients took up VLDL, becoming DiI + . At 24 hours post injection, ~95% of the DiI + monocytes became CD11c + , suggesting that VLDL uptake, which would cause foamy monocyte formation, induced monocyte phenotypic change to CD11c + . Along with the early appearance of CD11c + foamy monocytes, atherosclerosis started early in apoE -/- mice on HFD. Proportions of CD11c + /CD11b + cells examined by flow cytometry and mRNA levels of CD11c and inflammatory markers such as IL-6 and IL-1β increased in aorta of apoE -/- mice within 3 weeks on HFD compared to those of apoE -/- mice on ND or of WT on ND or HFD. In vitro assay revealed that foamy monocytes adhered more avidly to VCAM-1 under fluid shear stress. In summary, appearance of foamy monocytes and aortic atherosclerotic lesions began early in apoE -/- mice fed HFD. Foamy monocytes may contribute to nascent atherosclerosis via infiltration into arterial wall and production of inflammatory markers.