CAD increases the long noncoding RNA PUNISHER in small extracellular vesicles and regulates endothelial cell function via vesicular shuttling

Mohammed Rabiul Hosen*, Qian Li, Yangyang Liu, Andreas Zietzer, Katharina Maus, Philip Goody, Shizuka Uchida, Eicke Latz, Nikos Werner, Georg Nickenig, Felix Jansen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

2 Citations (Scopus)

Abstract

Long noncoding RNAs have emerged as biomarkers and regulators of cardiovascular disease. However, the expression pattern of circulating extracellular vesicle (EV)-incorporated lncRNAs in patients with coronary artery disease (CAD) is still poorly investigated. A human lncRNA array revealed that certain EV-lncRNAs are significantly dysregulated in CAD patients. Circulating small EVs (sEVs) from patients with (n=30) or without (n=30) CAD were used to quantify PUNISHER, GAS5, MALAT1, and H19 RNA levels. PUNISHER (p=0.002) and GAS5 (p=0.02) were significantly increased in patients with CAD, compared to non-CAD patients. Fluorescent labeling and RT-qPCR of sEVs demonstrated that functional PUNISHER was transported into the recipient cells. Mechanistically, the RNA-binding protein, hnRNPK, interacts with PUNISHER, regulating its loading into sEVs. Knockdown of PUNISHER abrogated the EV-mediated effects on EC migration, proliferation, tube formation, and sprouting. Angiogenesis-related gene profiling showed that the expression of VEGFA RNA was significantly increased in EV-recipient cells. Protein stability and RNA-immunoprecipitation indicated that the PUNISHER-hnRNPK axis regulates the stability and binding of VEGFA mRNA to hnRNPK. Loss of PUNISHER in EVs abolished the EV-mediated promotion of VEGFA gene- and protein expression. Intercellular transfer of EV-incorporated PUNISHER promotes a pro-angiogenic phenotype via a VEGFA-dependent mechanism.
Original languageEnglish
JournalMolecular Therapy - Nucleic Acids
Volume25
Pages (from-to)388-405
Number of pages18
DOIs
Publication statusPublished - 3 Sep 2021

Bibliographical note

© 2021 The Authors.

Keywords

  • angiogenesis
  • cardiovascular disease
  • coronary artery disease
  • extracellular vesicles
  • long noncoding RNA

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