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2017 Cardiovascular Research Day Abstract Book

97 Anti-ApoA-I

97 Anti-ApoA-I antibodies induced using an epitope-specific immunostimulatory liposomal formulation exacerbate atherosclerosis in dyslipidemic mice David Henson 1 • Robert Kline IV, MS 1 • Vincent Venditto, PhD 1 1Pharmaceutical Sciences, University of Kentucky Graduate Student Autoantibodies targeting apolipoprotein A-I (ApoA-I) have been identified in patients with chronic inflammatory diseases including rheumatoid arthritis, lupus and obesity and correlate with cardiovascular disease progression. Although correlated, the exact role of these antibodies has not been fully elucidated. Induction of antibodies in mice through immunization, rather than passive administration of antibodies derived from other species, offers a unique opportunity to explore the impact of anti-ApoA-I antibodies in the context of atherosclerosis. Furthermore, the ability to modulate epitope-specific immune responses offers a strategy to study the impact of antibody responses toward specific domains within the full protein. To achieve these objectives, we prepared an immunostimulatory liposomal formulation containing peptides derived from the LCAT domain of ApoA-I. We first determined that mice immunized with the complete formulation induce robust antibody responses toward the epitope, as well as the full-length protein. These data suggest that antibody responses toward ApoA-I are either not controlled by immunological tolerance mechanisms or our formulation was capable of breaking tolerance. Although successful at inducing a robust immune response, the antibodies alone failed to induce atherosclerosis in wild-type mice. We then studied the role of antibodies in the context of dyslipidemia utilizing the AAV-PCSK9 gainof-function mutant and western diet. After establishment of dyslipidemia, mice were immunized with the immunostimulatory liposomal formulations. Once again, mice immunized with the complete formulation achieved robust antibody responses, which persisted for 150 days. Furthermore, mice immunized with the complete formulation had a statistically significant elevation in atherosclerosis over control mice. These data highlight our ability to modulate the anti- ApoA-I antibody response using epitope-specific liposomal formulations and provides a platform to study the role of these antibodies in an immunologically intact system. This work was supported by a pilot grant through the Center for Research in Obesity & Cardiovascular Disease COBRE, NIH (P20GM103527) and a Scientist Development Grant from the American Heart Association (17SDG32670001). DH is supported by a UK Center for Clinical and Translational Science training grant from the National Center for Advancing Translational Sciences, NIH (TL1TR001996). 113

98 HDL-miR-223 Communication Pathway in vivo. Carrie Wiese 1 • Leslie Roteta 1 • Ryan Allen, PhD 2 • Wanying Zhu 2 • Kasey Vickers, PhD 2 1Molecular Physiology & Biophysics, Vanderbilt University • 2 Cardiovascular Medicine, Vanderbilt University Medical Center Graduate Student High-density lipoproteins (HDL) stably transport microRNAs (miRNAs) through the blood and facilitate a HDL-miRNA communication pathway. Previously, we demonstrated that macrophages and other myeloid cells export miR-223 to HDL in vitro. Furthermore, HDL-miRNAs, including miR- 223, are delivered to recipient human coronary artery endothelial cells (HCAECs) where miR-223 is not transcribed. Upon transfer of miR-223 to endothelial cells, the validated miR-223 target intracellular adhesion molecule 1 (Icam-1) expression is significantly suppressed. While HDLmiRNA transfer and cellular gene regulation have been demonstrated in vitro, intercellular communication has not been established in vivo. We utilized bone marrow transplantation between C57/B6J (WT) and Mir223-/- mice to define the physiological role of HDL-miRNA pathway in regulating cellular gene expression. To restore the HDL-miR-223 communication pathway within Mir223-/- mice, we transplanted WT bone marrow into lethally irradiated Mir223-/- mice resulting in a significant increase in HDL-miR-223 levels. Subsequently, a significant increase in miR-223 was identified in recipient tissues including whole liver, hepatocyte isolates, and aortic endothelium. Conversely, HDL-miR-223 pathway was depleted by transplanting Mir223-/- bone marrow into lethally irradiated WT mice, which resulted in a significant reduction of miR-223 on HDL. The reduction in HDL-miR-223 levels correlated with reduced miR-223 levels in recipient cells including endothelial and hepatocyte. Furthermore, altering miR-223 levels in endothelial cells and hepatocytes resulted in altered mRNA levels of putative targets, which we have validated as miR- 223 targets. In conclusion, myeloid cells export miR-223 to extracellular carriers such as HDL, which results in delivery of miR-223 to recipient cells where it regulates gene expression. 114

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