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CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate

Yi-Hong Wen1,2, Heng-Li Zhao2, Shao-Yu Wu2

  • 1School of Medicine, South China University of Technology, Guangzhou, 510006, China.

Acta Pharmacologica Sinica
|March 12, 2025
PubMed

Insights

SARS-CoV-2 circular RNAs (circRNAs) can damage endothelial cells by activating the TLR4/NF-κB/ROS pathway. This study identifies circSARS-CV2-N1368 as a key player in COVID-19 related cardiovascular issues.

Area of Science:

  • Cardiovascular Biology
  • Molecular Virology
  • Cellular Biology

Background:

  • SARS-CoV-2 infection is linked to cardiovascular complications.
  • Circular RNAs (circRNAs) encoded by SARS-CoV-2 are implicated.
  • The specific role of SARS-CoV-2 circRNAs in cardiovascular sequelae is largely unknown.

Purpose of the Study:

  • To investigate the functional effects of exogenous SARS-CoV-2 circRNAs on endothelial cells (ECs) and cardiovascular function.
  • To elucidate the molecular mechanisms underlying circRNA-induced endothelial damage.
  • To identify potential therapeutic targets for COVID-19 associated cardiovascular issues.

Main Methods:

  • Identification and functional analysis of SARS-CoV-2 derived circRNAs (circSARS-CV2-Ns) in ECs.
  • Assessment of platelet-endothelial cell interactions and vascular relaxation.
  • Evaluation of EC proliferation, migration, angiogenesis, and cardiac organoid beating.
  • Mechanistic studies involving microRNA (miR-103a-3p) sponging, target gene identification (ATF7, TLR4), and signaling pathway analysis (NF-κB, ROS).
  • In vitro experiments using reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC).

Main Results:

  • CircSARS-CV2-N1368 enhanced platelet adhesion to ECs and inhibited vascular relaxation.
  • Exogenous circSARS-CV2-N1368 suppressed EC proliferation, migration, angiogenesis, and cardiac organoid beating.
  • CircSARS-CV2-N1368 acted as a sponge for miR-103a-3p, reversing EC damage.
  • ATF7 was identified as a target of miR-103a-3p, and TLR4 as a downstream mediator.
  • The TLR4/NF-κB/ROS pathway was critical for circSARS-CV2-N1368-induced oxidative damage in ECs.
  • NAC treatment mitigated circSARS-CV2-N1368-induced EC impairment.

Conclusions:

  • SARS-CoV-2 encoded circRNAs, specifically circSARS-CV2-N1368, contribute to endothelial dysfunction.
  • CircSARS-CV2-N1368 exacerbates cardiovascular sequelae through the TLR4/NF-κB/ROS signaling pathway.
  • Targeting this pathway may offer therapeutic strategies for managing COVID-19 related cardiovascular complications.
Keywords:
SARS-CoV-2circular RNAendothelial cellsmiR-103a-3preactive oxygen species

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