2017 Cardiovascular Research Day Abstract Book

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55 ATF6 proteins regulate cardiac hypertrophy during pressure overload in the mouse heart Robert Correll, PhD 1 • Jeffrey Lynch, PhD 1 • Michelle Sargent 1 • Allen York 1 • Jeffery Molkentin, PhD 1 1Molecular <strong>Cardiovascular</strong> Biology, Cincinnati Children's Hospital Postdoc Objective: The activating transcription factor 6 (ATF6) branch of the endoplasmic reticulum (ER) unfolded protein response (UPR) plays a critical protective role in the heart’s response to acute injury or long-term hemodynamic stress that results in cardiac hypertrophy. Here we seek to elucidate the molecular mechanisms by which engagement of ATF6 proteins results in protective signaling in the context of pressure overload in the mouse heart. Methods and Results: Overexpression of thrombospondin-4 (Thbs4) results in a protective ER stress response and mice gene-deleted for Thbs4 demonstrated compromised ER stress signaling, inhibition of ATF6α processing and nuclear localization, and decreased survival after transverse aortic constriction (TAC) or myocardial infarction (MI) surgery. Using gene-deleted mice lacking ATF6α we demonstrate that Thbs4-mediated upregulation of ER protein chaperone expression and expansion of the ER compartment requires ATF6α expression. Furthermore, mice lacking ATF6α or the related protein ATF6β show defects in the hypertrophic response after pressure overload, leading to accelerated decompensation and failure after long-term TAC surgery, accompanied by reduced expression of ER protein chaperones. Conclusion: We find that both ATF6α and ATF6β proteins are required for compensatory hypertrophy and ER chaperone mobilization following pressure overload in the mouse heart. We hypothesize that the inability to upregulate chaperone expression during pressure overload results in diminished ER protein folding capacity that impairs the hypertrophic response. These results position ATF6 proteins as essential regulators of compensatory cardiac hypertrophy following chronic hemodynamic stress. 71
56 Isolation and characterization of primary bone marrow mesenchymal stem cells. Eman El-sawalhy, MD 1 • Lakshman Chelvarajan, PhD 2 • Ahmed Abdel-Latif, MD, PhD 1 1Division of <strong>Cardiovascular</strong> Medicine, Gill Heart Institute, University of Kentucky • 2 Saha cardiovascular research center, University of Kentucky Postdoc •Introduction: Myocardial infarction remains a major clinical problem and the leading cause of mortality in the world. Bone marrow derived stem cells have the capacity to participate in cardiac repair and regeneration of compromised heart muscle. The aim of this study is to generate highly enriched mesenchymal stem cells to inject 3x106 into the hearts of mice recovering from a myocardial infarction. •Methods: We isolated bone marrow (BM) from crushed long bones and hip bones of 6-8 weeks old GFP positive mice (C57BL/6). The stem cells were cultured in MesenCult media supplemented with MesenPure. Cells were cultured under either normoxic or hypoxic conditions (4% O2) for about two weeks. The cultures were then passaged when they reached 80% confluence. The cells were analyzed by flow cytometry using mesenchymal stem cell (CD90.2 and SCA-1) and hematopoietic (CD45) markers. •Results: As expected, the baseline bone marrow cells were negative for both stem cell markers, CD90 and Sca-1, while expressing the hematopoietic marker, CD45 (80%). During early expansion all the CD45– cells were Sca1+CD90–. Following subsequent passaging of the enriched cells, they began to express CD90. By the end of the second passage, the proportion of Sca1+CD90+ mesenchymal stem cells was 65%, while cells expressing Sca-1 alone was down to 32%. Most of the live healthy cells remained GFP+ throughout the expansion and passaging. Conclusion: Mesenchymal stem cells can be isolated and enriched from murine bone marrow in sufficient amounts to be used in our in vivo study to enhance regeneration of cardiomyocytes and restore cardiac function after myocardial infarction. 72
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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
Page 21 and 22: 4 Identification of a Lipid Signatu
Page 23 and 24: 6 Serum Amyloid A Activates the NLR
Page 25 and 26: 8 Azithromycin Therapy Reduces Card
Page 27 and 28: 10 Evidence of Angiotensin II-depen
Page 29 and 30: 12 Auditory Entrainment of Respirat
Page 31 and 32: 14 Cardiac specific Rad knockout In
Page 33 and 34: 16 Hypercholesterolemia Induces Acu
Page 35 and 36: 18 A Novel Approach for Modifying I
Page 37 and 38: 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: 54 Impact of miR-33 antagonism on m
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 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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