The interaction of lipid-poor HDL apolipoproteins which cells stimulates secretion of excess cholesterol by an active Golgi-dependent pathway controlled by an ABC transporter called ABC1. This pathway generates particles containing lipids and cellular vesicular transport proteins such as betaCOP and appears to depend on cellular proteoglycans. The secreted betaCOP-containing particles become associated with a subst of plasma HDL that binds heparin. Thus, lipid-poor apolipoproteins remove cellular lipids and proteins by a complex secretory pathway that generates particles that may transiently bind to arterial matrix proteoglycans. Our hypothesis is that the interaction of apolipoproteins with arterial cells protects against atherosclerosis by multiple mechanisms, including removing excess cellular cholesterol and producing particles that interfere with binding of atherogenic lipoproteins to arterial proteoglycans. We will define the biochemical and morphological properties of the apolipoprotein-mediated secretory pathway in fibroblast, cultured arterial smooth muscle cells, and macrophages, and we will characterize factors that regulate this pathway in these different cells. We will also conduct studies to identify and characterize cellular proteins and proteoglycans that regulate this pathway in these different cells. We will also conduct studies to identify and characterize cellular proteins and proteoglycans that are regulated., transported, and/or secreted in response to cellular apolipoprotein interactions. Lastly, we will characterize the binding of secreted and plasma betaCOP-containing particles to proteoglycans and identify the heparin and proteoglycan binding protein(s) in betaCOP- containing particles. These studies will define in more detail the properties of the apolipoprotein-mediated secretory pathway in arterial wall cells and provide more insight into mechanisms by which this pathway protects against atherosclerotic. An understanding of the cellular and extracellular mechanisms that underlie the anti-atherogenic effects of HDL apolipoproteins may suggest extracellular mechanisms that underlie the anti-atherogenic effects of HDL apolipoproteins may suggest therapeutic interventions for preventing and regressing cardiovascular disease.
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