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

Francesca Fasolo; Greg Winski; Zhaolong Li; Zhiyan Wu; Hanna Winter; Julia Ritzer; Nadiya Glukha; Joy Roy; Rebecka Hultgren; Jessica Pauli; Albert Busch; Nadja Sachs; Christoph Knappich; Hans-Henning Eckstein; Reinier A Boon; Valentina Paloschi; Lars Maegdefessel

doi:10.1016/j.omtn.2023.08.017

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

Mol Ther Nucleic Acids. 2023 Aug 17:33:848-865. doi: 10.1016/j.omtn.2023.08.017. eCollection 2023 Sep 12.

Authors

Francesca Fasolo^{1

2}, Greg Winski³, Zhaolong Li^{1

2}, Zhiyan Wu^{1

2

4}, Hanna Winter^{1

2}, Julia Ritzer¹, Nadiya Glukha¹, Joy Roy^{5

6}, Rebecka Hultgren^{5

6}, Jessica Pauli^{1

2}, Albert Busch^{1

7}, Nadja Sachs¹, Christoph Knappich¹, Hans-Henning Eckstein¹, Reinier A Boon^{8

9

10

11}, Valentina Paloschi^{1

2}, Lars Maegdefessel^{1

2

3}

Affiliations

¹ Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
² German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 10785 Berlin, Germany.
³ Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.
⁴ Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology and Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, P.R. China.
⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
⁶ Department of Vascular Surgery, Karolinska University Hospital, 17176 Stockholm, Sweden.
⁷ Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, Carl Gustav Carus and University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, Germany.
⁸ German Center for Cardiovascular Research DZHK 10785 Berlin, Partner Site Frankfurt Rhine-Main, Frankfurt am Main, Germany.
⁹ Institute of Cardiovascular Regeneration, Goethe University, 60590 Frankfurt am Main, Germany.
¹⁰ Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, 1081 Amsterdam, the Netherlands.
¹¹ Amsterdam Cardiovascular Sciences, Microcirculation, 1081 Amsterdam, the Netherlands.

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.

Keywords: ATM; MT: Non-coding RNAs; abdominal aortic aneurysm; apoptosis; biomarker; circular RNA; doxorubicin; oxidative stress; smooth muscle cells.