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Senescent cardiac fibroblasts-derived extracellular vesicles induced autophagy in cardiac fibroblasts via suppression of ras homolog enriched in brain like 1

  • 0Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
Journal of Pharmacological Sciences +

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March 22, 2025

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March 22, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Senescent cardiac fibroblast extracellular vesicles (EV) induce autophagy in other cardiac cells. This occurs through the transfer of specific microRNAs (miRNAs) that suppress Rhebl1 protein expression, promoting autophagy.

Area Of Science

  • Cardiovascular Biology
  • Cellular Senescence
  • Extracellular Vesicle Biology

Background

  • Cardiac fibroblasts (CFs) are crucial for myocardial tissue structure.
  • Cellular senescence is a stable cell cycle arrest.
  • Extracellular vesicles (EV) mediate intercellular communication via microRNA (miRNA) transfer.

Purpose Of The Study

  • To investigate the mechanisms by which doxorubicin-induced senescent CF-derived EV (D10^3-EV) induce autophagy in CFs.
  • To identify specific miRNAs within D10^3-EV responsible for autophagy induction.

Main Methods

  • Induction of cellular senescence in neonatal rat CFs (NRCFs) using doxorubicin (DOX).
  • Isolation and characterization of EV from NRCF culture media.
  • miRNA profiling of EV using miRNA-seq.
  • Analysis of target genes and protein expression (RHEBL1, LC3) in NRCFs treated with D10^3-EV.

Main Results

  • D10^3-EV exhibited altered miRNA profiles, with 14 miRNAs significantly increased compared to control EV.
  • Rhebl1 was identified as a target gene of the upregulated miRNAs.
  • D10^3-EV treatment increased LC3-II/LC3-I ratio and decreased RHEBL1 protein levels in NRCFs.
  • siRNA-mediated knockdown of Rhebl1 promoted an increase in LC3-II/LC3-I.

Conclusions

  • Senescent NRCF-derived EV induce autophagy in recipient NRCFs.
  • This autophagy induction is mediated by the suppression of Ras homolog enriched in brain like 1 (RHEBL1) protein expression via specific EV- miRNAs.
  • This study elucidates a novel mechanism of intercellular communication in cardiac senescence involving EV and miRNA-mediated gene silencing.

Keywords:

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