Abstract 14868: Loss of C-kit Exacerbates Atherosclerosis and Increases Ly-6chi Monocytes Despite Defective Medullary Myelopoiesis
Introduction: High numbers of pro-inflammatory monocytes have been associated with atherosclerosis in humans and hypercholesterolemic animals. This study assesses how the c-Kit modifies atherosclerotic pathology and monopoiesis in ApoE knockout (KO) mice.
Methods and Results: c-Kit deficient ApoE KO mice (ApoE KO KitW/Wv ) developed 2.5-fold more atherosclerotic lesions after consuming a western diet for 16 wks than their wild-type littermates (affected proportion of the aorta: 0.25 ± 0.03 vs.0.104 ± 0.01, p= 0.0002). Atherosclerosis in these mice was associated with elevated plasma levels of G-CSF, IL-6 and TNF-α, and a high number of circulating monocytes as determined by FACS (CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo). These monocytes were mostly pro-inflammatory, positive for Ly-6C. The Ly-6Chi/Ly-6Clo ratio was 5-fold higher in ApoE KO KitW/Wv than in ApoE KO Kit+/+ mice. Conversely, both groups of mice were monocytopenic with normal circulating levels of pro-inflammatory cytokines when fed a regular chow. Interestingly, hyperlipidemic ApoE KO KitW/Wv mice failed to expand the bone marrow-derived population of common myeloid progenitor cells (Lin-Kit+Sca-) in response to hyperlipidemia, which indicates an extra-medullary origin for monocytes in c-Kit deficient mice. In support of the latter observation, the spleens of ApoE KO KitW/Wv mice after consuming a western diet for 16 wks were twice as large and contained more F4/80+ macrophages than those of the wild-type littermates.
Conclusions: These results evidenced the importance of extra-medullary hematopoiesis in the genesis of circulating monocytes when medullary myelopoiesis is impaired.
- © 2013 by American Heart Association, Inc.