Abstract 327: Liver X Receptors (LXR) Modulate the Negative Effects on Endothelial Progenitors Cells after Feeding a High Cholesterol Diet

Abstract

The liver X receptors (LXRα/β) belong to the nuclear receptor superfamily of ligand activated transcription factors. LXRs are endogenously activated by oxysterols; and one of their primary functions is to facilitate cholesterol efflux out of cells, such as macrophages, via the ABCA1 & ABCG1 transporters. Bone marrow (BM) transplant studies have shown that LXRs are important for preventing the formation of atherosclerotic plaques. Loss of LXRs in the monocyte/macrophage population of the BM was thought to be the primary mediator of the increased atherosclerosis in these studies. However, the BM is comprised of a variety of cell types that are differentiated from hematopoietic stem cells (HSCs). Like numerous other vascular complications, endothelial defects are central to the pathogenesis of the early stages of atherosclerosis. Endothelial progenitor cells (EPCs), derived from HSCs in the BM, contribute to vascular health primarily through the secretion of factors that maintain and repair the endothelium of the damaged vasculature. We hypothesized that LXRs also modulate the negative effects of cholesterol on EPCs, in addition to its effects in macrophages. To study the effects of dietary cholesterol on EPCs and the roles of LXRs in modulating these effects, WT and LXRα/β-/- mice were fed a high-fat/high-cholesterol (HF/HC) diet starting at 8-9 weeks of age for a total of 12 weeks. Complete blood counts showed that in the LXRα/β-/- but not the WT mice fed the HF/HC diet, there was a significant expansion of select myeloid populations (neutrophils, monocytes, platelets). Furthermore, EPCs derived from the HF/HC fed LXRα/β-/- mice had a higher expression of the endothelial markers CD144 and VEGFR2 compared to WT mice and LXRα/β-/- mice on chow diet, suggesting enhanced differentiation to a more endothelial-like cell in the absence of LXRs. Notably, the paracrine reparative actions of EPCs have been shown in populations of cells with low expression of endothelial markers. Taken together, these results suggest that LXRs modulate the effects of HF/HC diet on the differentiation of EPCs to endothelial cells and thus, may provide another cell type within the BM that would benefit from LXR activation in modulating vascular disease.[[Unable to Display Character:  ]]