Atherosclerosis is a complex pathological process that results from an interplay of genetic and environmental components. Although several risk factors for disease development (e.g., plasma cholesterol, blood pressure) have been described, many human beings develop accelerated atherosclerosis in the absence of known risk factors. It has been proposed that some individuals may be genetically predisposed to develop atherosclerosis as a result of mechanisms operating at the level of the arterial wall. Proliferation of smooth muscle cells in the arterial intima is of key importance in the development and growth of atherosclerotic lesions. In the proposed study the hypothesis to be tested is that genetic susceptibility to atherosclerosis at the artery wall level includes a differential proliferative response of smooth muscle cells manifested through a regulatory molecule heparan sulfate proteoglycan (HS-PG). The studies are possible because of the availability of a genetically selected atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeon. Through an unknown mechanism(s) the smooth muscle cells of the atherosclerosis-susceptible WC pigeon demonstrate a greater proliferation capacity in culture. Preliminary examination of cell surface proteoglycans has demonstrated a reduction in HS-PG in WC compared to SR cells, and structural variations in the HS-PG isolated from the two cell types. Through a series of studies outlined in this proposal, the structure, amount and metabolic properties of the cell surface HS-PG will be characterized and compared in cultured aortic smooth muscle cells of WC and SR pigeons. Radioactive precursors and the new technique of oligosaccharide mapping will be used to determine whether structural diversities result in altered functional properties of the HS-PG molecule in these cells. The detailed structure of the HS chain will be examined. Pulse chase and kinetic modeling techniques will be sued to describe the metabolic and cellular pathways characteristic for the cell surface HS-PG and to define the role of HS-PG in regulation of the WC and SR smooth muscle cell proliferative state and potential. The ultimate goal of the proposal is to determine the role of HS-PG in relation to cell proliferation in the atherosclerosis-susceptible pigeon as a model for human atherosclerosis.
Showing the most recent 10 out of 11 publications
