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2017 Cardiovascular Research Day Abstract Book

55 ATF6 proteins

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 Cardiovascular 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 Cardiovascular 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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