In mouse models of atherosclerosis, HDL is thought to be atheroprotective because it removes excess cholesterol from macrophages of the artery wall and inhibits inflammation. We have shown that HDL inhibits a specific inflammatory pathway in macrophages - the type I interferon response pathway - that is regulated by TLR4-TRAM signaling. We also have demonstrated that elevated levels of the acute-phase response proteins SAA1 and SAA2 (SAA1/2) in human HDL associate with impaired sterol efflux from macrophages. Recent studies demonstrate that the sterol efflux capacity of human serum HDL strongly associates with CAD status but is independent of HDL-cholesterol and protein (apoA-I) levels. Thus, the cholesterol efflux capacity of serum HDL might be a marker-and perhaps mediator-of atherosclerotic burden that is independent of HDL- C and apoA-I. Changes in the HDL proteome could alter its ability to remove cellular cholesterol or inhibit macrophage inflammation. We therefore will test the hypotheses that (a) HDL prevents macrophage activation by inhibiting the TLR4-TRAM pathway and (b) altered levels of pro- and anti-inflammatory proteins render HDL dysfunctional in mice and humans.

Public Health Relevance

Cardiovascular disease (CAD) is the leading cause of death in industrialized Western populations. Moreover, inflammation-a central theme of this proposal-is implicated in the pathogenesis of many other human diseases. The population at large might benefit from the proposed studies because we may identify ways to identify subjects at risk for CAD, which might lead to preventative treatment. In the long-term, it is possible that the studies outlined in this proposal might lead to the development of new therapeutic interventions designed to prevent or treat CAD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL108897-01A1
Application #
8323850
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2012-04-16
Project End
2016-03-31
Budget Start
2012-04-16
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$431,875
Indirect Cost
$181,875
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
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
Hutchins, Patrick M; Heinecke, Jay W (2015) Cholesterol efflux capacity, macrophage reverse cholesterol transport and cardioprotective HDL. Curr Opin Lipidol 26:388-93
Vaisar, Tomáš; Tang, Chongren; Babenko, Ilona et al. (2015) Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity. J Lipid Res 56:1519-30
Ronsein, Graziella E; Pamir, Nathalie; von Haller, Priska D et al. (2015) Parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) exhibit comparable linearity, dynamic range and precision for targeted quantitative HDL proteomics. J Proteomics 113:388-99
Pamir, Nathalie; Liu, Ning-Chun; Irwin, Angela et al. (2015) Granulocyte/Macrophage Colony-stimulating Factor-dependent Dendritic Cells Restrain Lean Adipose Tissue Expansion. J Biol Chem 290:14656-67
Shao, Baohai; de Boer, Ian; Tang, Chongren et al. (2015) A Cluster of Proteins Implicated in Kidney Disease Is Increased in High-Density Lipoprotein Isolated from Hemodialysis Subjects. J Proteome Res 14:2792-806
Heinecke, Jay W (2015) Small HDL promotes cholesterol efflux by the ABCA1 pathway in macrophages: implications for therapies targeted to HDL. Circ Res 116:1101-3

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