Lipid-transport independent cell signaling properties of apolipoprotein E in protection against vascular occlusive diseases:

Apolipoprotein (apo) E is a 34-kDa protein associated with several classes of plasma lipoproteins, including chylomicrons, VLDL, and HDL. Research in the past two decades has clearly established the importance of apoE level and structure in protection against vascular disease. However, most of the previous studies have focused on the role of apoE as a cholesterol transport protein and its function in protecting the vessel wall against excessive cholesterol deposition. Our laboratory demonstrated that apoE has additional lipid transport-independent functions in the vessel wall. Our working hypothesis is that the vascular protective effects of apoE are also mediated via its binding to specific cell surface receptors on smooth muscle cells, each transmitting distinct signals that result in inhibition of growth factor-induced cell migration, proliferation, and excessive extracellular matrix synthesis and deposition. Our current projects include:

1) Testing the hypothesis that apoE interaction with low density lipoprotein receptor-related protein 1 (LRP-1), heparan sulfate proteoglycans, and apoE receptor-2 on smooth muscle cells each activating distinct signaling pathways that results in inhibition of cell migration, proliferation, and matrix deposition, respectively. These events are all necessary and act in combination to limit vascular occlusion after endothelial damage in vivo.

2) Identify the cell signaling mechanisms by which apoE binding to LRP-1 results in inhibition of smooth muscle cell migration. Specifically, we propose that apoE binding to LRP-1 activates protein kinase A signaling pathway and as a consequence results in inhibition of cell migration.

3) Identify the mechanism by which apoE binding to another receptor, namely apoE receptor-2, results in inhibition of excessive extracellular matrix deposition. DNA microarray and proteomics approach will be used to identify signal transduction mechanism by which apoE binding to apoE receptor-2 results in inhibition of matrix production.

4) Identify the specific cell surface heparan sulfate proteoglycan responsible for apoE inhibition of early cell signaling events that are required for cell proliferation.

Information obtained from these studies not only will extend our current understanding on the role of apoE in vascular protection, but will also contribute toward understanding the overall pathogenic mechanisms associated with neointimal hyperplasia in the vessel wall. The information will be valuable in designing optimal therapeutic strategy to limit vascular occlusion due to neointimal hyperplasia.