2017 Cardiovascular Research Day Abstract Book

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83 Deoxysphingolipids - mediators in taxane-induced peripheral neuropathy Katrin Anne Becker, PhD 1 • Anne-Kathrin Uerschels, MD 2 • Jacek Bielawski, PhD 3 • Joan Colglazier 4 • Erhard Bieberich, PhD 5 • Erich Gulbins, PhD 1 • Stefka Spassieva, PhD 5 1Molecular Biology , University of Duisburg-Essen • 2 Neurosurgery, University of Duisburg-Essen • 3Biochemistry and Molecular Biology , Medical University of South Carolina • 4 Medicine, Medical University of South Carolina • 5 Physiology, University of Kentucky Faculty Taxanes are chemotherapy drugs used in wide variety of cancers. However, there efficacy can be hindered by a major dose limiting side effect - peripheral neuropathy. Although, the clinical symptoms of taxane-induced peripheral neuropathy are well documented, the molecular mechanism is currently not well understood and there are no treatment options available. In our previous work, we have shown that in the plasma of breast cancer patients treated with taxane, the levels of minor class of lipids, the deoxysphingolipids, were associated with incidence and severity of neuropathy (Kramer et al, FASEB J, 2015). In our current study, we used a mouse model to test whether taxane treatment results in increased levels of deoxysphingolipids in the dorsal root ganglia and spinal cord. Mice were three times intraperitoneally injected with taxane. Lipids were extracted from the isolated ganglia and spinal cord and subjected to quantitative mass spectrometry analyses. We observed significant elevation of deoxysphingolipid levels only in the dorsal root ganglia. In addition, we compared in vitro in neuronal cultures, the toxic effect of deoxysphingosine, a deoxysphingolipid, and sphingosine, a structurally similar sphingolipid. Importantly, our in vitro data showed that only deoxysphingosine treatment resulted in morphological changes and toxicity in the neurons. Taken together our data suggest that in the dorsal root ganglia, the neurotoxic effect of the systemic taxane treatment is likely mediated by deoxysphingolipids. 99
84 Reduced Low-Density Lipoprotein Receptor-Related Protein-1 in Mature Mice Modestly Effects Hypercholesterolemia and Atherosclerosis Shayan Mohammadmoradi, MS 1 • Deborah A. Howatt 1 • Anju Balakrishnan 1 • Jessica J. Moorleghen 1 • Mark Graham 2 • Adam Mullick 2 • Hong Lu, PhD 1 • Alan Daugherty, PhD, DSc 1 1Saha <strong>Cardiovascular</strong> <strong>Research</strong> Center, University of Kentucky • 2 Ionis Pharmaceuticals Graduate Student Background and Objectives: Low-density lipoprotein receptor-related protein-1 (LRP1) has been hypothesized to serve as a receptor for the removal of selected lipoprotein particles from plasma. However, mice with somatically engineered mutation of LRP1 have not provided a clear understanding of the specific lipoprotiens that are regulated by LRP1. Therefore, the aim of this study was to reduce LRP1 using antisense oligomers in mature mice to determine effects on lipoprotein metabolism and atherosclerosis. Methods and Results: LRP1 antisense oligonucleotide (ASO; 50 mg/kg, injected once per week) or its control ASO was administered subcutaneously to 8-week old male low-density lipoprotein (LDL) receptor deficient mice (n=10/each group). All groups were fed a saturated fat-enriched diet for 8 weeks started 1 week after the first injection of ASOs. There was no difference in body weight between the two groups. Profound reduction of LRP1 was confirmed by qPCR and Western blotting. Whole body inhibition of LRP1 elicited a modestly increased total plasma cholesterol compared to its control group. Size exclusive chromatography analyses demonstrated the increased cholesterol was due to increased VLDL and LDL-cholesterol. Despite augmented hypercholesterolemia, whole body inhibition of LRP1 did not increase atherosclerotic lesion size. LRP1 was also reduced in a hepatocyte-specific manner by administration of an LRP1 ASO coupled with GalNac to target the asialofeutin receptor. LDL receptor deficient mice were injected with GalNAc LRP1 ASO or its control ASO (5 mg/kg/week). Hepatic-specific inhibition of LRP1 did not change plasma cholesterol concentration, lipoprotein distribution and atherosclerosis. Conclusion: Profound reductions of LRP1 in mature mice modestly increased hypercholesterolemia and had no effect on atherosclerosis in LDL receptor deficient mice. 100
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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
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22 Regulation of Akt Signaling by N
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24 Vascular Inflammatory Regulation
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26 Vascular inflammation induced ex
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28 Sexual Dimorphism of Angiotensin
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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 and 90: 72 Increased Circulating Trimethyla
Page 91 and 92: 74 Circulating Bacterial Small RNA
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: 82 Protease-activated Receptor 2 De
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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