Particular number of high-density lipoproteins (HDL) levels correlate inversely with atherosclerosis. HDL functions may contribute to this anti-atherogenic effect include: efflux of cholesterol from tissue, inhibition of lipid peroxidation, and inhibition of inflammation. Transfer of microRNA (miRNA) by HDL to endothelium may contribute to inhibition of inflammation by HDL. For reasons that remain unclear, in certain clinical conditions HDL loses its ability to perform these functions and become pro inflammatory instead. Currently, there are no interventions to prevent or reverse HDL dysfunction Interestingly, a sensitive indicator of lipid peroxidation, the F2-isoprostanes (F2-IS0P), are found at higher levels in HDL than in LDL or other components of plasma. Peroxidation of HDL in vitro renders it dysfunctional, and chemical modification of the lysyl residues of apoAl, the major protein of HDL, can dramatically alter its function. Isolevuglandins (IsoLG) are endogenous y-ketoaldehydes formed in parallel with F2-IS0P during lipid peroxidation. IsoLG rapidly modify and crosslink lysyl residues of proteins as well as phosphatidylethanolamines (PE). We hypothesize that IsoLG mediate HDL dysfunction in diseases associated with an increased risk of atherosclerosis and that small molecule aldehydes scavengers that we have previously developed to block IsoLG from modifying proteins will protect against HDL dysfunction.
The specific aims ofthe application will test the following hypothesis: Hypothesis 1: Modification of HDL with Fa-isoP or IsoLG renders HDL dysfunctional. In this aim, we will determine if treatment with synthetic IsoLG and F2-IS0P alters HDL function and structure, and expression of efflux protein in macrophages. We will also test if aldehydes scavengers protect against myeloperoxidase induced HDL dysfunction in vivo. Hypothesis 2: Formation of antibodies against IsoLG-apoAl contribute to HDL dysfunction. In this aim, we will determine the relationship between IsoLG-apoAl antibody titers and HDL function in rheumatoid arthritis patients. We will also test if inducing antibodies to IsoLG-ApoAl can cause HDL dysfunction in mice. Hypothesis 3: Modification of HDL alters its capacity to accept and deliver anti-inflammatory miRNA. In this aim, we will examine the effect of HDL modification on macrophage expression and export of miRNA, as well as uptake by endothelial cells.

Public Health Relevance

High density lipoproteins (HDL) are important in suppressing the development of atherosclerosis but can become dysfunctional under certain conditions where oxidative stress also occurs. Oxidation of lipids can generate reactive compounds, called isolevuglandins, which can react with proteins in HDL and render it dysfunctional. This application will address the hypothesis that overproduction of isolevuglandins is responsible for rendering HDL dysfunctional.

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National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Vanderbilt University Medical Center
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