Diabetes is a chronic inflammatory state that is associated with an increased risk of cardiovascular disease.Evidence is accumulating that the inflammatory protein, serum amyloid A (SAA), plays an important role inthe pathogenesis of atherosclerosis. SAA has several biological functions that could potentially be involvedin atherogenesis, including its ability to bind and be retained by vascular proteoglycans and to recruitinflammatory cells such as monocytes. The studies outlined propose to investigate the role of elevatedlevels of SAA in the pathogenesis of macrovascular disease in diabetes, and to evaluate potentialmechanisms by which SAA affects the atherogenic process. To that end we propose to determine theatherogenic potential of SAA in apo B-containing lipoproteins and HDL in mouse models of both type 2 andtype 1 diabetes, to establish whether deficiencies of SAA1 and SAA2, the major inducible circulating forms ofSAA, affect plasma lipoprotein composition and function, and atherosclerosis in a mouse model of insulinresistance and type 2 diabetes, and to investigate the role of local over-expression of inducible SAA isoformsin macrophages on atherogenesis in LDLR-/- mice fed a diabetogenic diet. Approaches that will be used willinclude in vitro studies to determine potential mechanisms whereby diabetes-induced increases in SAAlevels affect biological processes involved in the pathogenesis of atherosclerosis. We also will usemolecular approaches to inhibit the elevation of SAA that occurs in response to a diabetogenic diet. This willallow us to evaluate the role of the major inducible forms of SAA to facilitate atherogenesis. Finally, we willuse a novel retroviral vector to selectively overexpress the various SAA isoforms in macrophages, includingmacrophages of the artery wall. This approach will allow us to determine whether the local overexpressionof SAA isoforms by macrophages increases atherosclerosis. Collectively these studies will allow us toevaluate potential mechanisms that links diabetes and atherosclerosis via an inflammatory pathway thatinvolves SAA in both type 1 and type 2 diabetes.
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