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

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.

The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

“…Fig. 1E ) 43 . To investigate the function of MIRIAL , we chose a loss-of-function approach using LNA gapmers in human umbilical vein endothelial cells (HUVECs), achieving a knockdown efficiency of approximately 80-88% ( Supp.…”

“…The related data are available on Gene Expression Omnibus (accession number GSE248795; reviewer token: cxutusselbenlkp; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE248795). Human aneurysmal abdominal arteries were harvested during OR in the Department of Vascular and Endovascular Surgery at the Klinikum rechts der Isar of the Technical University Munich and previously published 43 . Single-cell RNA sequencing and analysis were performed as described 43 .…”

“…Human aneurysmal abdominal arteries were harvested during OR in the Department of Vascular and Endovascular Surgery at the Klinikum rechts der Isar of the Technical University Munich and previously published 43 . Single-cell RNA sequencing and analysis were performed as described 43 . The related data are available on Gene Expression Omnibus (accession number GSE237230).…”

Utilization of an Artery‐on‐a‐Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases

“…Moreover, as the non-diseased vessel (Ctrl) and diseased (Plaque) were independently prepared for individual scRNA-seq datasets from the same patients, CRYAB and INHBA expression level was compared in Fibro-SMC clusters of the two groups and found more expressed in the cell clusters of non-diseased arteries (Figure 4D). Similarly, In the AAA scRNA-seq dataset, [34] CRYAB and INHBA are enriched in structural cell clusters (Figure S6D, Supporting Information) and more highly expressed in the non-dilated SMC cluster compared to the SMC obtained from the dilated aorta (Figure S6E,F, Supporting Information).…”

Loss of Smooth Muscle Tenascin-X Inhibits Vascular Remodeling Through Increased TGF-β Signaling

“…We downloaded RNA-sequencing data sets of aortic SMCs from 3 healthy donors or 5 patients with AAA (GSE237229 from the National Center for Biotechnology Information Gene Expression Omnibus database and Table S4 in the study by Fasolo et al 30 ) and of thoracic aortic media tissue from 6 control donors with cardiomyopathy undergoing cardiac transplantation or 8 patients with thoracic aortic aneurysm and dissection (Tables S7 and S8 in the study by Liu et al 31 ). Raw counts of TNXB (ENSG00000168477) were reanalyzed with the Prism 8 software (GraphPad).…”