This application is submitted in response to PA-11-012-Toward an improved understanding of HDL- which states """"""""The ultimate goal of this FOA is to develop reproducible and robust assays to measure HDL function and to identify novel genes and pathways related to HDL function."""""""" We believe we are well-qualified to address this need because our research program has focused on understanding the factors that contribute to the cardioprotective effects of HDL. Two key components of our approach have centered on (i) investigating the factors that control cholesterol efflux and HDL's ability to inhibit macrophage inflammation, and (ii) developing mass spectrometric approaches for quantifying oxidation products and proteins in HDL. Importantly, we have identified specific mechanism that may impair the cardioprotective effects of HDL. One involves oxidative damage of apoA-I (the major HDL protein) by myeloperoxidase (MPO). MPO impairs apoA-I's ability to remove cholesterol from macrophages by the ABCA1 pathway. Another potential mechanism involves alterations in the anti-inflammatory proteins that are carried by HDL. Using shotgun proteomics, we have demonstrated that HDL carries a unique cargo of proteins in cardiovascular disease (CVD) subjects and that those proteins might make previously unsuspected contributions to HDL's function. Moreover, we have shown that HDL of subjects with CVD or acute inflammation exhibts impaired ability to remove cholesterol from macrophages, the key first step in reverse cholesterol transport. Our studies will take advantage of three unique human populations. The first involves control subjects, subjects with acute coronary syndrome, and subjects with established CVD. The second involves control subjects and subjects with CVD enrolled in a prospective trial of statin therapy. The third population took part in a prospective study of subjects with carotid artery disease that was evaluated for atherosclerotic progression by MRI. The availability of these valuable resources will enable us to investigate specific mechanisms for generating dysfunctional HDL in subjects with CVD, the leading cause of death in industrialized societies.
Identifying proteins that alter HDL's function and are selectively enriched or depleted in subjects at risk for CVD would support the hypothesis that inflammation converts human HDL to a dysfunctional form. Our long-term goal is to understand the factors that impair HDL's ability to remove cholesterol and inhibit macrophage inflammation, which may have important implications for HDL therapeutics.
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|Melchior, John T; Walker, Ryan G; Cooke, Allison L et al. (2017) A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state. Nat Struct Mol Biol 24:1093-1099|
|Ronsein, Graziella E; Heinecke, Jay W (2017) Time to ditch HDL-C as a measure of HDL function? Curr Opin Lipidol 28:414-418|
|Pamir, Nathalie; Hutchins, Patrick M; Ronsein, Graziella E et al. (2017) Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI Insight 2:|
|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|
|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|
|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|
|Hutchins, Patrick M; Heinecke, Jay W (2015) Cholesterol efflux capacity, macrophage reverse cholesterol transport and cardioprotective HDL. Curr Opin Lipidol 26:388-93|
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