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PreprintCited by 12Cardiac Fibrosis and RemodelingCardiac Ischemia and ReperfusionRNA Interference and Gene Delivery

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Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

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Ibrahim, Ahmed Gamal-Eldin, Ciullo, Alessandra, Miyamoto, Kazutaka, Liao, Ke, Jones, Xaviar M., Yamaguchi, Shukuro, Li, Chang, Rannou, Alice, Nawaz, Asma, Morris, Ashley, Tsi, Kara, Marbán, Cristina H., Lee, Jamie, Manriquez, Nancy, Hong, Yeojin, Kumar, Arati Naveen, Dawkins, James F., Rogers, Russell G., Marbán, Eduardo·2024·Science Translational Medicine
DOI 10.1101/2024.02.20.581294PMC PMC11257602

Preprint — published as 10.1126/scitranslmed.adp1338 · Paper page

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Abstract

Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates TREX1, an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia/reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed either to TY1 or TREX1. Inhibition of TREX1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for TREX1, TY1 attenuated DNA damage in the post-MI heart. This novel mechanism—pharmacologic upregulation of TREX1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. One Sentence Summary: Upregulation of three prime exonuclease, TREX1, in macrophages enhances tissue repair post myocardial infarction.

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Metadata

Authors
Ibrahim, A. G.-E., Ciullo, A., Miyamoto, K., Liao, K., Jones, X. M., Yamaguchi, S., Li, C., Rannou, A., Nawaz, A., Morris, A., Tsi, K., Marbán, C. H., Lee, J., Manriquez, N., Hong, Y., Kumar, A. N., Dawkins, J. F., Rogers, R. G., & Marbán, E.
Affiliations
Cedars-Sinai Medical Center (US)
Corresponding author
Ibrahim, Ahmed Gamal-Eldin
ORCID
Venue
Science Translational Medicine
Publisher
openRxiv
Published
2024-02-22
Volume
17
Issue
827
Pages
eadp1338-eadp1338
ISSN
1946-6234 (ISSN-L)
DOI
10.1101/2024.02.20.581294
PMC
PMC11257602
OpenAlex
W4416965440
Cited by
12
References
1
Citations by year
2026: 8 · 2025: 2 · 2024: 2
FWCI
6.99
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • California Institute for Regenerative Medicine (TRAN1-15317)
  • Cedars-Sinai Medical Center
  • National Heart, Lung, and Blood Institute (R01HL142579, R01HL164588, R01HL164896, T32HL116273)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
TREX1, Y RNA, myocardial infarction, myocardial ischemia-reperfusion injury, macrophages, extracellular vesicles, cardioprotection, disease-modifying therapy

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