DESCRIPTION (provided by applicant): Recently, high-density lipoproteins (HDL) were discovered to transport microRNAs to cells, leading to altered gene expression. HDL-miRNA cargo and its delivery to target cells can be altered by different disease states and may be responsible for some disease sequelae. A common disease sequela of rheumatoid arthritis (RA) is cardiovascular (CV) disease, which is increased two-fold, but underlying mechanisms are unclear. A potential mechanism is delivery of altered HDL-miRNA cargo to cells that promote vascular inflammation and endothelial dysfunction. Currently, nothing is known about HDL-miRNA cargo and its transfer in RA. The overarching hypothesis is that in RA altered HDL-miRNA cargo transfer modulates the responses of cells that promote vascular inflammation and endothelial dysfunction, which are common in RA and occur early in CV disease development. The rationale for the proposed research is that miRNAs are powerful gene expression regulators, and several miRNAs are altered in both RA and CV disease. HDL interacts with only a small proportion of cells, facilitating a unique accumulation of miRNAs. Moreover, HDL is capable of targeted miRNA delivery specifically to cells of the immune system and endothelial cells. Building on preliminary data, Aim 1 will define the HDL-miRNA cargo in RA by comparing the cargo of patients with RA without coronary artery disease (CAD), patients with RA with CAD, and control subjects, and by determining which miRNAs are associated with inflammation and endothelial function in RA. Aim 2 will define the differential transfer (RA vs control) of HDL- miRNAs to macrophages and their impact on macrophages inflammatory cytokine expression and on plaque inflammation and atherosclerosis. Aim 3 will define the differential transfer (RA vs control) of HDL-miRNAs to endothelial cells and their impact on adhesion molecule expression and nitric oxide bioavailability, and on atherosclerosis. The proposed research is significant because it mechanistically addresses how cellular functions, which are important in the pathogenesis of CV disease, are altered through a novel mechanism (HDL-miRNA transfer) that could be modified. Moreover, this proposal is innovative because it will be the first to examine HDL-miRNAs in RA and has wide implications for future investigations that are not limited to the development of CV disease in RA. This study is high impact because it could identify fundamental, targetable mechanisms underlying early vascular changes which promote CV disease in RA, and could lead to targeted miRNA therapeutics.