Cytoplasmic nucleic acid-based XNAs directly enhance live cardiac cell function by a Ca 2+ cycling-independent mechanism via the sarcomere.

Autor: Thompson BR; Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States of America., Soller KJ; Department of Chemistry, University of Minnesota, Minneapolis, MN, United States of America., Vetter A; Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States of America., Yang J; Department of Chemistry, University of Minnesota, Minneapolis, MN, United States of America., Veglia G; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, United States of America., Bowser MT; Department of Chemistry, University of Minnesota, Minneapolis, MN, United States of America., Metzger JM; Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States of America. Electronic address: metzgerj@umn.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2019 May; Vol. 130, pp. 1-9. Date of Electronic Publication: 2019 Mar 05.
DOI: 10.1016/j.yjmcc.2019.02.016
Abstrakt: Nucleic acid - protein interactions are critical for regulating gene activation in the nucleus. In the cytoplasm, however, potential nucleic acid-protein functional interactions are less clear. The emergence of a large and expanding number of non-coding RNAs and DNA fragments raises the possibility that the cytoplasmic nucleic acids may interact with cytoplasmic cellular components to directly alter key biological processes within the cell. We now show that both natural and synthetic nucleic acids, collectively XNAs, when introduced to the cytoplasm of live cell cardiac myocytes, markedly enhance contractile function via a mechanism that is independent of new translation, activation of the TLR-9 pathway or by altered intracellular Ca 2+ cycling. Findings show a steep XNA oligo length-dependence, but not sequence dependence or nucleic acid moiety dependence, for cytoplasmic XNAs to hasten myocyte relaxation. XNAs localized to the sarcomere in a striated pattern and bound the cardiac troponin regulatory complex with high affinity in an electrostatic-dependent manner. Mechanistically, XNAs phenocopy PKA-based modified troponin to cause faster relaxation. Collectively, these data support a new role for cytoplasmic nucleic acids in directly modulating live cell cardiac performance and raise the possibility that cytoplasmic nucleic acid - protein interactions may alter functionally relevant pathways in other cell types.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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