2017 Cardiovascular Research Day Abstract Book

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95 Targeting of HB-EGF against hypertension and renal damage Lihua Yang, MS 1 • Seonwook Kim 1 • Debra Rateri 1 • Richard Lee, PhD 2 • Mark Graham, PhD 2 • Sangderk Lee, PhD 1 1Saha Cardiovascular Research Center, University of Kentucky • 2 Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals Staff Study goal: Previous reports suggested that the heparin binding EGF-like growth factor (HB-EGF), which is an EGFR ligand, is positively involved in the development of renal disease. In this study, we tested the effects of the HB-EGF targeting using antisense oligonucleotide (ASO) administration on the blood pressure and renal damage induced by AngII infusion in mouse model systems. Experimental design and results: To test the effects of the HB-EGF ASO administration on the AngIIinduced hypertension, C57BL/6 mice (male, 10 weeks of age) were pretreated with control and HB- EGF ASO for 2 weeks and cotreated with AngII infusion (1,000ng/min/kg) for additional 4 weeks. We monitored blood pressure changes during 6 weeks using standard tail-cuff procedure. We observed that the HB-EGF ASO administration significantly downregulated basal and AngII-induced blood pressure in the system. The HB-EGF targeting also reduced the kidney size. To test the effects of the HB-EGF targeting on the renal damage, the LDLR KO mice (male, 16 weeks of age) were pretreated with control and HB-EGF ASO and cotreated with high fat diet (HFD; 42% calorie from fat, 0.2% cholesterol) and AngII-infusion (1,000ng/min/kg) for additional 4 weeks. At the termination step, we compared plasma creatinine and BUN levels as markers of the status of the renal damage. The result showed that the HB-EGF ASO administration effectively protected against HFD and AngII-induced renal damage in the mouse model system. Conclusion: These results suggested that the HB-EGF signaling positively involved in regulating blood pressure and renal damage. The targeting of the HB-EGF signaling might be an approach to delay the development of the hypertension associated with renal damage. 111
96 HB-EGF is a Key Positive Regulator of Hepatic VLDL Secretion Seonwook Kim 1 • Lihua Yang, MS 1 • Debra Rateri 1 • Ryan Temel, PhD 1 • Richard Lee, PhD 2 • Mark Graham, PhD 2 • Sangderk Lee, PhD 1 1Saha Cardiovascular Research Center, University of Kentucky • 2 Cardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals Staff Study goal: Unbalanced hepatic VLDL production (assembly/secretion) is a risk factor for the development of hypertriglyceridemia or non-alcoholic fatty liver disease (NAFLD) under metabolic stress conditions like metabolic syndrome. Previous reports showed that the circulatory heparinbinding EGF-like growth factor (HB-EGF), which is a ligand of EGFR, is correlated with cholesterol level and risk of coronary artery disease in human. From these previous data, we tested the hypothesis that the HB-EGF signaling is a positive regulator of VLDL production in the liver. Experimental procedure and results: In Hep-G2 cells, the recombinant HB-EGF induced increase of the apoB secretion, which is an essential component of VLDL particle. In C57BL/6 mice, the administration of recombinant HB-EGF increased hepatic VLDL secretion; in contrast, the HB-EGF antisense oligonucleotide (ASO) administration or the tail-vein injection of EGFR blocker BIBX1382 induced significant suppressions of the hepatic VLDL secretion. The HB-EGF ASO administration effectively downregulated circulatory lipid levels (TG and cholesterol) associated with VLDL particles in multiple mouse strains (C57BL/6, LDLR KO, and apoE KO). At the same time, the targeting induced accumulation of neutral lipids in the liver, specifically, TG and cholesterol ester. Conclusion: These results indicate that the HB-EGF signaling positively regulates VLDL secretion in the liver under normal and metabolic stress condition. Future study of the interaction with insulin signaling for the regulation would be interesting in understand the pathology of metabolic symptom. 112
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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
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32 PCB 126 Exposure Increases Perip
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34 Endothelial Mineralocorticoid Re
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36 Optimization of immunomagnetic s
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38 Gestational Diabetes Provokes Po
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40 The Prognostic Role of Elevated
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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 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: 94 Impact of miR-33 antagonism on c
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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