Abstract 20428: The Impact of Deletion of ABCA1 and ABCA7 in Bone Marrow-Derived Cells on Platelet Function and Atherosclerosis in LDL Receptor Knockout Mice
Objective: ABCA1 and ABCA7 regulate cholesterol and phospholipid export from cells. In addition, ABCA7 facilitates clearance of apoptotic cells. Specific disruption of ABCA1 in bone marrow-derived cells (BMDCs) results in an increased susceptibility to atherosclerosis. We aimed to assess the effects of specific deletion of ABCA7 alone or combined with ABCA1 in BMDCs on platelet function and atherosclerosis.
Methods: Chimeras with dysfunctional ABCA1 and/or ABCA7 in BMDCs were generated by transplantation of bone marrow from ABCA1 knockout (KO), ABCA7 KO, or ABCA1/ABCA7 double knockout (dKO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. To induce atherosclerosis, the transplanted LDLr KO mice were fed a Western-type diet for 10 weeks.
Results: Disruption of ABCA7 in BMDCs did not affect foam cell formation in the peritoneal cavity nor atherosclerotic lesion development, possibly due to compensatory upregulation of ABCA1. However, disruption of ABCA1 or ABCA1/ABCA7 resulted in increased atherosclerotic lesion development, which was positively correlated with the amount of foam cells in the peritoneal cavity. Interestingly, severe splenomegaly combined with white foci was observed in dKO transplanted mice, which was consistent with extreme lipid accumulation in spleens. In addition, spleens of dKO transplanted mice showed a reduction in T-cells. Disruption of ABCA7 in BMDCs also caused thrombocytopenia, while the platelet counts of ABCA1 KO and dKO transplanted mice were not affected. Disruption of platelet ABCA7 inhibited the ex vivo aggregation response after stimulation by either ADP or collagen, whereas ABCA1 deletion only affected ADP-induced aggregation. Aggregation of dKO platelets was only reduced after stimulation by collagen.
Conclusions: ABCA7 does not affect atherosclerotic lesion development either in the absence or presence of ABCA1 despite its anticipated role in phagocytosis and lipid efflux. However, it is essential for normal platelet counts and platelet function. Moreover, combined deletion of ABCA1 and ABCA7 in hematopoietic cells causes severe splenomegaly and a decreased amount of splenic T cells, suggesting the importance of ABCA1 and ABCA7 for maintaining a healthy spleen morphology.
- © 2010 by American Heart Association, Inc.