2017 Cardiovascular Research Day Abstract Book

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73 A specific rotamer of apolipoprotein A-I enables Lecithin-cholesterol acyl transferase activation by discoidal HDL Allison L. Cooke 1 • Jamie C. Morris 1 • John T. Melchior, PhD 1 • Rong Huang, PhD 1 • W. Gray Jerome, PhD 2 • Scott E Street 1 • W. Sean Davidson, PhD 1 1Pathology, University of Cincinnati • 2 Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center Graduate Student Investigating the structure of apolipoprotein (apo)A-I, the primary protein component of high density lipoprotein (HDL), is important for understanding how HDL interacts with lipid-modifying proteins to mediate its cardioprotective functions in plasma. HDL lipid discs contain two molecules of apoA-I arranged in an antiparallel, stacked ring-structure. ApoA-I is composed of 10 tandem, amphipathic, alpha-helical repeats that encapsulate lipid for plasma transport on the hydrophobic face of the ring-structure, and allows HDL to interact with modifying proteins on the hydrophilic face. For example, lecithin-cholesterol acyl transferase (LCAT) is a critical lipoprotein-associated enzyme that converts cholesterol to cholesterol ester for transport out of peripheral cells. It was hypothesized that changing the orientation of apoA-I on HDL discs can modulate LCAT reactivity. To test this, site-directed cysteine-point mutagenesis was used to generate different orientations (rotamers) of apoA-I on HDL discs of similar size and composition: K133C- helix 5 of one apoA-I molecule adjacent to helix 5 of its antiparallel partner (5/5 rotamer), K206C- helix 5 adjacent to helix 2 (5/2 rotamer), and K195C-helix 5 adjacent to helix 1 (5/1 rotamer). Initially, an LCAT activation assay revealed LCAT had significantly increased reactivity to discs with the 5/5 rotamer relative to wild-type or the other rotamers (p
74 Circulating Bacterial Small RNA Bound to LDL Induce Inflammatory Activation of Macrophages Ryan Allen, PhD 1 • Shilin Zhao, PhD 2 • Marisol Ramirez, MS 1 • Bradley Richmond, MD, PhD 3 • Timothy Blackwell, MD 3 • Quanhu Sheng, PhD 2 • Kasey Vickers, PhD 1 1<strong>Cardiovascular</strong> Medicine, Vanderbilt University Medical Center • 2 Center for Quantitative Sciences, Vanderbilt University Medical Center • 3 Allergy and Inflammation, Vanderbilt University Medical Center Postdoc Chronic, sub-acute inflammation is an active component of many human diseases of diverse etiology, characterized by sustained recruitment and activation of macrophages. Macrophages are phagocytic, myeloid-derived cells that are resident in nearly every tissue to provide innate defense against invasive pathogens. Upon injury, macrophages respond to remove damaged cells and cell debris and facilitate tissue repair. However, in disease, prolonged activation of macrophages promotes tissue remodeling, often to the detriment of tissue function. This is classically observed in the development of atherosclerosis, in which monocytes infiltrate the artery wall, differentiate to macrophages, and phagocytize LDL to become cholesterol-engorged “foam cells”, which rapidly develop a pro-inflammatory phenotype that contributes to further cardiovascular disease. Our lab previously reported that high-density lipoproteins (HDL) traffic miRNAs between cells as part of intercellular gene-regulation networks that we proposed could mediate anti-inflammatory properties of HDL. Although low-density lipoproteins (LDL) have also been reported to traffic miRNA, more recent data from small-RNA sequencing (sRNA-SEQ) indicates that LDL-associated sRNA are primarily exogenous, with most sRNA fragments originating from bacteria. Most interestingly, taxonomic analysis of bacteria contributing sRNA to the LDL pool revealed a profile distinct from any characterized profile of the comprehensive human microbiome. Additionally, antibiotic mediated ablation of the gut microbiome failed to disrupt lipoprotein-sRNA pools of mice, suggesting that bacterial sRNA fragments are not linked to the gut microbiome. However, manipulation of housing conditions was capable of inducing stark changes in the landscape of bacterial sRNA bound to lipoproteins of mice, indicative of a potential role for the environment in shaping the lipoprotein-sRNA fingerprint. In support of this, we characterized the lipoprotein-sRNA profiles of wild-type and polymeric IgA receptor deficient (Pigr-/-) mice, a model of compromised airway mucosal immunity, and found reduced abundance of bacterial sRNA fragments, most notably of Proteobacteria and Firmicutes. Although many potential functions remain to be explored, we hypothesized that exogenous sRNA associated with LDL may influence the inflammatory potential of LDL upon uptake by artery-wall macrophages by activation of endosomal, nucleic acidsensing toll-like receptors (TLR), which are highly expressed in macrophages and facilitate innate immunity. To test this hypothesis, we treated primary mouse macrophages and PMA-stimulated THP1 cells with physiologically relevant concentrations of fresh, native LDL (nLDL) and observed induction of pro-inflammatory cytokine expression. Strikingly, partial silencing of nucleic acidsensing TLRs blunted this nLDL induced activation of pro-inflammatory gene expression. Conversely, treatment of human hepatoma cells, which express low levels of exogenous RNAsensing TLRs, with nLDL failed to induce pro-inflammatory cytokine expression. Taken together, our data identify a novel, non-lipid cargo of LDL that is capable of modulating inflammatory gene expression in macrophages and may contribute to the pathogenesis of atherosclerosis, and many other metabolic diseases. 90
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Cardiovascular Research Day ABSTRAC
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SCHEDULE FOR THE DAY Friday, Novemb
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SCHEDULE FOR THE DAY continued Frid
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2017 GILL HEART INSTITUTE YOUNG INV
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FEATURED SPEAKER Calum MacRae, M.D.
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SPECIAL PRESENTATION Mark Stoops He
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NOTES 12
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2017 POSTER PARTICIPANTS 40 Mohamed
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2017 ABSTRACTS 16
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2 Inhibition of Megalin Reduces Ath
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4 Identification of a Lipid Signatu
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6 Serum Amyloid A Activates the NLR
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8 Azithromycin Therapy Reduces Card
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10 Evidence of Angiotensin II-depen
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12 Auditory Entrainment of Respirat
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14 Cardiac specific Rad knockout In
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16 Hypercholesterolemia Induces Acu
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18 A Novel Approach for Modifying I
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20 Clinical Use of the Amplatzer Se
Page 39 and 40: 22 Regulation of Akt Signaling by N
Page 41 and 42: 24 Vascular Inflammatory Regulation
Page 43 and 44: 26 Vascular inflammation induced ex
Page 45 and 46: 28 Sexual Dimorphism of Angiotensin
Page 47 and 48: 30 Computational modeling of amylin
Page 49 and 50: 32 PCB 126 Exposure Increases Perip
Page 51 and 52: 34 Endothelial Mineralocorticoid Re
Page 53 and 54: 36 Optimization of immunomagnetic s
Page 55 and 56: 38 Gestational Diabetes Provokes Po
Page 57 and 58: 40 The Prognostic Role of Elevated
Page 59 and 60: 42 Lysophosphatidic Acid Receptor 4
Page 61 and 62: 44 Recapitulating In Vivo Fibroblas
Page 63 and 64: 46 Sex-Specific Differences in Card
Page 65 and 66: 48 Ticagrelor Reduces Inflammation
Page 67 and 68: 50 Association between Plasma Chole
Page 69 and 70: 52 Does Light Pollution Affect the
Page 71 and 72: 54 Impact of miR-33 antagonism on m
Page 73 and 74: 56 Isolation and characterization o
Page 75 and 76: 58 The XY sex chromosome complement
Page 77 and 78: 60 CHROME: a Long Non-coding RNA th
Page 79 and 80: 62 Making Good: Secretory Quality C
Page 81 and 82: 64 Thrombospondin 1 (TSP1) Deficien
Page 83 and 84: 66 Serum Amyloid A3 is a High Densi
Page 85 and 86: 68 Adipocyte deficiency of ACE2 inc
Page 87 and 88: 70 Hypercholesterolemia-induced end
Page 89: 72 Increased Circulating Trimethyla
Page 93 and 94: 76 Pancreatic Beta Cell Export of m
Page 95 and 96: 78 Understanding inhibition of lipo
Page 97 and 98: 80 Insulin signaling regulates apol
Page 99 and 100: 82 Protease-activated Receptor 2 De
Page 101 and 102: 84 Reduced Low-Density Lipoprotein
Page 103 and 104: 86 Pharmacological inhibition of Hu
Page 105 and 106: 88 The Effects of Hypercholesterole
Page 107 and 108: 90 Reduced HDL in mice overexpressi
Page 109 and 110: 92 Human Antigen R (HuR) Regulates
Page 111 and 112: 94 Impact of miR-33 antagonism on c
Page 113 and 114: 96 HB-EGF is a Key Positive Regulat
Page 115 and 116: 98 HDL-miR-223 Communication Pathwa
Page 117 and 118: 100 Short-Term Exercise Training Di
Page 119 and 120: 102 The Ral-Exocyst Pathway Regulat
Page 121 and 122: NOTES 120
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2017 Cardiovascular Research Day Abstract Book

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