Anti-atherogenic functions of high-density lipoproteins (HDL) include mediation of reverse cholesterol transport and reduction of oxidation and inflammation. Mounting evidence supports the concept that dysfunctional HDL loses its beneficial properties and actually contributes to the development of atherosclerosis. The central theme of our PPG is that HDL function is a critical determinant of atherogenesis and cardiovascular risk in chronic human disease. The goal of our research is to define the mechanisms for HDL functional loss in three diseases associated with increased risk for atherosclerotic cardiovascular disease: Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of our proposal is that inflammation and oxidative stress impair HDL function. Plasma levels of F2-isoprostanes (F2-lsoP) are accurate in vivo markers of lipid peroxidation. Interestingly, HDL is the main carrier of F2-lsoP in plasma. Our studies in RA subjects suggest that F2-lsoP may be a biomarker for HDL function. Isolevuglandins (IsoLG) are a group of highly reactive mediators of oxidative damage that are formed as products of the IsoP pathway. We will examine the novel hypothesis that IsoLG forms adducts to HDL proteins and lipids, impairing HDL function. Subjects with FH have elevated levels of F2-lsoP and IsoLG protein adducts in their HDL and strikingly impaired anti-inflammatory HDL function. Chronic kidney disease (CKD) has been associated with increased plasma F2-lsoP levels and reduced cholesterol efflux capacity of HDL isolated from subjects with ESRD. HDL is also the major carrier of microRNAs (miRNAs) in plasma and delivers them to cells impacting gene expression. We will examine the novel hypothesis that the HDL-miRNA profile differs with disease state is altered by oxidative stress, and impacts HDL function. Projects 1 and 2 will examine mechanisms of dysfunctional HDL formation in FH and CKD, respectively. Project 3 will examine the impact of IsoP products on HDL function. The projects will rely heavily on Cores providing assays for HDL function, isoprostane products, miRNAs and bioinformatics. Ultimately, we aim to develop novel biomarkers and therapeutic approaches for dysfunctional HDL, shifting the clinical paradigm.
The goal of our research is to define the mechanisms for HDL dysfunction in three distinct diseases: Familial Hypercholesterolemia (FH), Rheumatoid Arthritis (RA), and End Stage Kidney Disease (ESRD), associated with increased risk for atherosclerotic cardiovascular disease. We will examine the hypothesis that bioactive lipids, including isoprostanes and isolevuglandins, and microRNA serve as biomarkers and/or mediators of HDL dysfunction. We aim to develop novel biomarkers and therapeutic approaches for dysfunctional HDL.
|Ormseth, Michelle J; Stein, C Michael (2016) High-density lipoprotein function in rheumatoid arthritis. Curr Opin Lipidol 27:67-75|
|Ormseth, Michelle J; Yancey, Patricia G; Solus, Joseph F et al. (2016) Effect of Drug Therapy on Net Cholesterol Efflux Capacity of High-Density Lipoprotein-Enriched Serum in Rheumatoid Arthritis. Arthritis Rheumatol 68:2099-105|
|Babaev, Vladimir R; Yeung, Michele; Erbay, Ebru et al. (2016) Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. Arterioscler Thromb Vasc Biol 36:1122-31|
|Michell, Danielle L; Vickers, Kasey C (2016) HDL and microRNA therapeutics in cardiovascular disease. Pharmacol Ther 168:43-52|
|Yang, Haichun; Fogo, Agnes B; Kon, Valentina (2016) Kidneys: key modulators of high-density lipoprotein levels and function. Curr Opin Nephrol Hypertens 25:174-9|
|Kon, Valentina; Linton, MacRae F (2016) HDL: Beyond Atheroprotection. J Am Soc Nephrol 27:341-4|
|Babaev, Vladimir R; Ding, Lei; Zhang, Youmin et al. (2016) Macrophage IKKÎ± Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis. Arterioscler Thromb Vasc Biol 36:598-607|
|Beavers, Kelsey R; Werfel, Thomas A; Shen, Tianwei et al. (2016) Porous Silicon and Polymer Nanocomposites for Delivery of Peptide Nucleic Acids as Anti-MicroRNA Therapies. Adv Mater 28:7984-7992|
|Cheung, Kei-Hoi; Keerthikumar, Shivakumar; Roncaglia, Paola et al. (2016) Extending gene ontology in the context of extracellular RNA and vesicle communication. J Biomed Semantics 7:19|
|Michell, Danielle L; Vickers, Kasey C (2016) Lipoprotein carriers of microRNAs. Biochim Biophys Acta 1861:2069-2074|
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