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.
- © 2013 by American Heart Association, Inc.