The major focus of this Program Project relates to the role of lipids and lipoproteins in initiating and regulating processes central to atherosclerosis, vascular calcification, and osteoporosis. During the current grant period we identified oxidized phospholipids which differentially regulate inflammatory responses and demonstrated the molecular mechanisms by which they increase monocyte binding to endothelial cells (EC). The IL-8 promoter element responsive to these oxidized lipids was different from those which respond to cytokines and LPS. An oral apoA-I mimetic peptide (D-4F) dramatically reduced atherosclerosis in LDL receptor null and apoE null mice independent of plasma or HDL-cholesterol levels. D-4F also prevented the increased macrophage traffic into arteries of LDL receptor null mice after a Western diet and influenza A infection. Matrix GLA protein was shown to regulate BMP-2 activity and an atherogenic diet induced osteoporosis in atherosclerosis suceptible but not atherosclerosis resistant mice. When a paraoxonase-1 (PON1) null mouse was constructed and bred on to an apoE null background atherosclerosis increased. Conversely, a transgenic mouse overexpressing PON1 was protected from atherosclerosis. A myeloperoxidase null mouse was constructed and surprisingly had increased atherosclerosis. The nuclear receptor LXR was shown to activate an internal promoter that produced a novel alternative form of human ABCG1. Macrophage cholesterol efflux was found to be controlled by LXRalpha. The farnesoid X-activated receptor (FXR) was shown to induce apoC-II. MRP2 was shown to be controlled by the nuclear receptors PXR, FXR, and CAR. The atherosclerosis susceptibility and resistance, respectively, of C57BL/6 and C3H/HeJ mice was shown to be due to differences in the response of their EC to mildly oxidized LDL and was independent of plasma lipids or macrophages. Using QTL analysis a segment on chromosome 6 of CAST/Ei mice was identified as being responsible for the dramatic resistance of these hyperlipidemic mice to atherosclerosis and 5-Lipoxygenase was identified as the responsible gene. Based on these findings we propose 7 Projects and 4 Cores for the next grant period. The proposed experiments will use biochemistry, cell biology, molecular biology, mouse genetics and genetically engineered mice to determine the molecular mechanisms by which lipids and lipoproteins cause atherosclerosis, vascular calcification and osteoporosis.
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