This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clinical studies have demonstrated an association between elevated levels of serum amyloid A (SAA) and increased risk of cardiovascular events. Moreover, elevated levels of SAA are also associated with obesity which is a significant risk factor for cardiovascular disease. Previous studies have demonstrated that plasma SAA concentrations correlate with atherosclerotic lesion size in hyperlipidemic mice. Preliminary data demonstrate that overexpression of SAA in apoE-/- mice increases atherosclerosis. To study the effect of obesity on atherosclerosis we have generated a model of diet induced obesity in apoE-/- mice. The induction of obesity and increase in atherosclerosis in this model are associated with an increase in plasma and adipose tissue SAA concentrations. A large percentage of plasma SAA was bound to the pro-atherogenic lipoproteins, VLDL and LDL, in obese apoE-/- mice compared to lean, in which SAA is primarily associated with HDL. Lipoprotein binding to proteoglycans in the subendothelial space is suggested to increase lipoprotein retention in the vascular wall and facilitate the development of atherosclerosis. SAA enriched HDL has increased binding to proteoglycans. Thus, SAA enrichment of VLDL and LDL may promote atherosclerosis by increasing lipoprotein retention in the vascular wall and facilitating foam cell formation. Therefore we propose that obesity induced inflammation augments adipose SAA production to increase atherosclerosis in apoE-/- mice. To test this hypothesis we propose to: 1) Determine if adipocytes and/or macrophages infiltrating the adipose tissue during obesity are the source of increased adipose tissue SAA expression. 2) Determine if macrophages infiltrating the adipose tissue regulate SAA adipocyte expression. 3) Determine if SAA enrichment of pro-atherogenic lipoproteins increases proteoglycan binding, thus facilitating macrophage foam cell formation. 4) Determine if SAA deficiency attenuates obesity-induced atherosclerotic lesion formation.
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