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)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Shao, Baohai; Heinecke, Jay W (2018) Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions? Expert Rev Proteomics 15:31-40
Basu, Debapriya; Hu, Yunying; Huggins, Lesley-Ann et al. (2018) Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor. Circ Res 122:560-567
Scolaro, Bianca; Nogueira, Marina S; Paiva, Aline et al. (2018) Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine. Mol Metab 11:137-144
Fang, Xiang; Dorcely, Brenda; Ding, Xi-Ping et al. (2018) Glycemic reduction alters white blood cell counts and inflammatory gene expression in diabetes. J Diabetes Complications 32:1027-1034
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
Bornfeldt, Karin E; Kramer, Farah; Batorsky, Anna et al. (2018) A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis. Am J Pathol 188:343-352
Basu, Debapriya; Huggins, Lesley-Ann; Scerbo, Diego et al. (2018) Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition. Arterioscler Thromb Vasc Biol 38:2207-2216
Subramanian, Savitha; Goodspeed, Leela; Wang, Shari et al. (2018) Deficiency of Invariant Natural Killer T Cells Does Not Protect Against Obesity but Exacerbates Atherosclerosis in Ldlr-/- Mice. Int J Mol Sci 19:
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
He, Yi; Kothari, Vishal; Bornfeldt, Karin E (2018) High-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus. Arterioscler Thromb Vasc Biol 38:e10-e16

Showing the most recent 10 out of 136 publications