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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Krishack, Paulette A; Sontag, Timothy J; Getz, Godfrey S et al. (2016) Serum amyloid A regulates monopoiesis in hyperlipidemic Ldlr(-/-) mice. FEBS Lett 590:2650-60
Ronsein, Graziella E; Hutchins, Patrick M; Isquith, Daniel et al. (2016) Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects. Arterioscler Thromb Vasc Biol 36:404-11
Shimizu-Albergine, Masami; Van Yserloo, Brian; Golkowski, Martin G et al. (2016) SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci U S A 113:E5685-93
Bornfeldt, Karin E (2016) Does Elevated Glucose Promote Atherosclerosis? Pros and Cons. Circ Res 119:190-3
Han, Chang Yeop (2016) Roles of Reactive Oxygen Species on Insulin Resistance in Adipose Tissue. Diabetes Metab J 40:272-9
Monette, Jeffrey S; Hutchins, Patrick M; Ronsein, Graziella E et al. (2016) Patients With Coronary Endothelial Dysfunction Have Impaired Cholesterol Efflux Capacity and Reduced HDL Particle Concentration. Circ Res 119:83-90
Ronsein, Graziella E; Reyes-Soffer, Gissette; He, Yi et al. (2016) Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone. Mol Cell Proteomics 15:1083-93
Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E et al. (2016) Serum amyloid A impairs the antiinflammatory properties of HDL. J Clin Invest 126:266-81
Tang, Chongren; Liu, Yuhua; Yang, Wendy et al. (2016) Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice. J Lipid Res 57:100-8
Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J (2016) Lipid Use and Misuse by the Heart. Circ Res 118:1736-51

Showing the most recent 10 out of 95 publications