Recent studies have supported the view that increased levels of Lp(a) are associated with increased risk of coronary artery disease and the accumulation of Apo(a) in the arterial wall. The principal goal of this proposal is to define the constituents involved in the interactions of Lp(a) with the subendothelial extracellular matrix and explore possible consequences of this interaction. This goal is based on the hypothesis: Lp(a)'s interactions with the subendothelial extracellular matrix accelerate the atherosclerotic process by contributing to the accumulation of cholesterol ester rich lipoproteins (ApoB-Lp) and hemostatic factors. To examine some aspects of this thesis, the following specific aims are presented:
Specific aim 1. Determine whether the binding of Lp(a) to the subendothelial extracellular matrix promotes the accumulation of other ApoB-containing lipoproteins.
Specific aim 2. Determine whether the binding of Lp(a) to the subendothelial extracellular matrix promotes the accumulation of various hemostatic factors (Factor VII, Protein C, prothrombin, tissue plasminogen activator, etc.).
Specific aim 3. Determine which constituents of the subendothelial extracellular matrix are responsible for the binding affinity of Lp(a).
Specific aim 4. Define the molecular basis for the interactions of Lp(a) with ApoB-containing lipoproteins and the subendothelial extracellular matrix.
Specific aim 5. Develop methodology and monitor the consequences of bound hemostatic factors at the lipoprotein-extracellular matrix interface. Electrophoretic analyses, biochemical separations, characterization of isolated lipoprotein species and extracellular components, cell biology, ligand and immunoblotting, monoclonal antibodies, tools and approaches of molecular biology, digital imaging for quantitative and binding analyses, and quantitative analyses of lipids and apolipoproteins are some of the methodologies which will be used to achieve these specific aims. This proposal should provide new insights into the relationship of Lp(a)/ Apo(a) and ApoB-containing lipoproteins to the subendothelial extracellular matrix in atherosclerosis. It should also give a better definition of the role of interactions of hemostatic factors with ApoB-containing lipoproteins and the particular domains of Apo(a) and ApoB that bind subendothelial extracellular matrix, hemostatic factors, and each other. These studies should provide a better understanding of the link between plasma lipoproteins, the hemostasis system, and the progression of atherosclerosis.
