The circular RNA Ataxia Telangiectasia Mutated regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Francesca Fasolo - , Technical University of Munich (Author)
  • Greg Winski - , Karolinska Institutet (Author)
  • Zhaolong Li - , Technical University of Munich (Author)
  • Zhiyan Wu - , Technical University of Munich (Author)
  • Hanna Winter - , Technical University of Munich (Author)
  • Julia Ritzer - , Technical University of Munich (Author)
  • Nadiya Glukha - , Technical University of Munich (Author)
  • Joy Roy - , Karolinska Institutet (Author)
  • Rebecka Hultgren - , Karolinska Institutet (Author)
  • Jessica Pauli - , Technical University of Munich (Author)
  • Albert Busch - , Department of Visceral, Thoracic and Vascular Surgery (Author)
  • Nadja Sachs - , Technical University of Munich (Author)
  • Christoph Knappich - , Technical University of Munich (Author)
  • Hans-Henning Eckstein - , Technical University of Munich (Author)
  • Reinier A Boon - , Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Valentina Paloschi - , Technical University of Munich (Author)
  • Lars Maegdefessel - , Technical University of Munich (Author)

Abstract

An abdominal aortic aneurysm (AAA) is a pathological widening of the aortic wall characterized by loss of smooth muscle cells (SMCs), extracellular matrix degradation, and local inflammation. This condition is often asymptomatic until rupture occurs, leading to high morbidity and mortality rates. Diagnosis is mostly accidental and the only currently available treatment option remains surgical intervention. Circular RNAs (circRNAs) represent a novel class of regulatory non-coding RNAs that originate from backsplicing. Their highly stable loop structure, combined with a remarkable enrichment in body fluids, make circRNAs promising disease biomarkers. We investigated the contribution of circRNAs to AAA pathogenesis and their potential application to improve AAA diagnostics. Gene expression analysis revealed the presence of deregulated circular transcripts stemming from AAA-relevant gene loci. Among these, the circRNA to the Ataxia Telangiectasia Mutated gene (cATM) was upregulated in human AAA specimens, in AAA-derived SMCs, and serum samples collected from aneurysm patients. In primary aortic SMCs, cATM increased upon angiotensin II and doxorubicin stimulation, while its silencing triggered apoptosis. Higher cATM levels made AAA-derived SMCs less vulnerable to oxidative stress, compared with control SMCs. These data suggest that cATM contributes to elicit an adaptive oxidative-stress response in SMCs and provides a reliable AAA disease signature.

Details

Original languageEnglish
Pages (from-to)848-865
Number of pages18
JournalMolecular therapy. Nucleic acids
Volume33
Publication statusPublished - 12 Sept 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10481153
Scopus 85169018563

Keywords

Sustainable Development Goals