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 in the pathogenesis of atherosclerosis. SAA has several biological functions that could potentially be involved in atherogenesis, including its ability to bind and be retained by vascular proteoglycans and to recruit inflammatory cells such as monocytes. The studies outlined propose to investigate the role of elevated levels of SAA in the pathogenesis of macrovascular disease in diabetes, and to evaluate potential mechanisms by which SAA affects the atherogenic process. To that end we propose to determine the atherogenic potential of SAA in apo B-containing lipoproteins and HDL in mouse models of both type 2 and type 1 diabetes, to establish whether deficiencies of SAA1 and SAA2, the major inducible circulating forms of SAA, affect plasma lipoprotein composition and function, and atherosclerosis in a mouse model of insulin resistance and type 2 diabetes, and to investigate the role of local over-expression of inducible SAA isoforms in macrophages on atherogenesis in LDLR-/- mice fed a diabetogenic diet. Approaches that will be used will include in vitro studies to determine potential mechanisms whereby diabetes-induced increases in SAA levels affect biological processes involved in the pathogenesis of atherosclerosis. We also will use molecular approaches to inhibit the elevation of SAA that occurs in response to a diabetogenic diet. This will allow us to evaluate the role of the major inducible forms of SAA to facilitate atherogenesis. Finally, we will use a novel retroviral vector to selectively overexpress the various SAA isoforms in macrophages, including macrophages of the artery wall. This approach will allow us to determine whether the local overexpression of SAA isoforms by macrophages increases atherosclerosis. Collectively these studies will allow us to evaluate potential mechanisms that links diabetes and atherosclerosis via an inflammatory pathway that involves SAA in both type 1 and type 2 diabetes.

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National Heart, Lung, and Blood Institute (NHLBI)
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University of Washington
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Ronsein, Graziella E; Heinecke, Jay W (2017) Time to ditch HDL-C as a measure of HDL function? Curr Opin Lipidol 28:414-418
Heinecke, Jay W; Bornfeldt, Karin E (2017) A Long Road Ahead for Discovering New HDL Metrics That Reflect Cardiovascular Disease Risk. J Am Coll Cardiol 70:179-181
Ronsein, Graziella E; Vaisar, Tomáš (2017) Inflammation, remodeling, and other factors affecting HDL cholesterol efflux. Curr Opin Lipidol 28:52-59
Wall, Valerie Z; Barnhart, Shelley; Kramer, Farah et al. (2017) Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (?C20)-acyl chains in macrophages. J Lipid Res 58:1174-1185
Pamir, Nathalie; Hutchins, Patrick M; Ronsein, Graziella E et al. (2017) Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI Insight 2:
Den Hartigh, Laura J; Omer, Mohamed; Goodspeed, Leela et al. (2017) Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity. Arterioscler Thromb Vasc Biol 37:466-475
Ruparelia, Neil; Chai, Joshua T; Fisher, Edward A et al. (2017) Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 14:133-144
Kraakman, Michael J; Lee, Man Ks; Al-Sharea, Annas et al. (2017) Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. J Clin Invest 127:2133-2147
Kothari, Vishal; Bornfeldt, Karin E (2017) Liver Kinase B1 Links Macrophage Metabolism Sensing and Atherosclerosis. Circ Res 121:1024-1026
Pamir, Nathalie; Hutchins, Patrick; Ronsein, Graziella et al. (2016) Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway. J Lipid Res 57:246-57

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