The circular RNA Ataxia-telangiectasia mutated (cATM) regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms

Fasolo, F.; Winsky, G.; Li, Z.; Wu, Z.; Winter, H.; Glukha, N.; Roy, J.; Hultgren, R.; Pauli, J.; Busch, A.; Sachs, N.; Knappich, C.; Eckstein, H.-H.; Boon, R.; Paloschi, V.; Maegdefessel, L.

doi:10.1101/2022.11.11.516115

bioRxiv · 10.1101/2022.11.11.516115

The circular RNA Ataxia-telangiectasia mutated (cATM) regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms

Fasolo, F.·Winsky, G.·Li, Z.·Wu, Z.·Winter, H.·Glukha, N.·Roy, J.·Hultgren, R.·Pauli, J.·Busch, A.·Sachs, N.·Knappich, C.·Eckstein, H.-H.·Boon, R.·Paloschi, V.·Maegdefessel, L.

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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 often accidental, and for now, the only available treatment option remains surgical intervention. Circular RNAs (circRNAs) are RNA loops that originated from backsplicing, which have received increasing attention as a novel class of functional non-coding RNAs contributing to cardiovascular physiology and disease. Their high structural stability, combined with a remarkable enrichment in body fluids, make circRNAs promising disease biomarkers. We aimed to investigate the contribution of circRNAs to AAA pathogenesis and their potential application as biomarkers for AAA diagnosis. Combined circRNA array and quantitative real-time PCR analysis revealed the presence of differentially expressed circular transcripts stemming from AAA-relevant gene loci. Among these, the circRNA to the Ataxia-telangiectasia mutated gene (cATM) was upregulated in human AAA tissue specimens, in AAA patient-derived SMCs, and serum samples collected from aneurysm patients. In control primary aortic SMCs, cATM increased upon angiotensin II stimulation, while its silencing triggered apoptosis. Furthermore, doxorubicin could induce cATM expression, supporting a link with acute stress response in SMCs. Constitutively higher cATM expressing AAA patient-derived SMCs were less vulnerable to oxidative stress-induced cell death and survival pathways enriched when compared to control SMCs. Taken together, this data supports the role of cATM in adapting SMCs to oxidative stress in the vascular AAA micromilieu. This molecular signature provides an additional parameter to be included in procedures for AAA screening in combination with already established practices.

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Fasolo, F., Winsky, G., Li, Z., Wu, Z., Winter, H., Glukha, N., Roy, J., Hultgren, R., Pauli, J., Busch, A., Sachs, N., Knappich, C., Eckstein, H.-H., Boon, R., Paloschi, V., Maegdefessel, L.. 2022-11-11. The circular RNA Ataxia-telangiectasia mutated (cATM) regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms. https://doi.org/10.1101/2022.11.11.516115

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