Spatial and Clinical Long Noncoding RNA Signatures Reveal Novel Regulators of Thoracic Aortic Aneurysm

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All articles of this category (opens in new window) Background: Thoracic aortic aneurysm (TAA) development involves multiple risk factors through incompletely understood mechanisms. Long noncoding RNAs (lncRNAs) have emerged as key regulators in cardiovascular pathophysiology and may explain differential TAA susceptibility. This study investigates lncRNA expression patterns and biological functions in TAA patients with varying risk profiles to identify potential novel therapeutic targets. Methods: We employed a four-step workflow analyzing aortic tissue from TAA patients and heart donors: (1) lncRNA identification using bulk and single-cell RNA sequencing, (2) qPCR validation of selected candidates, (3) stratified analysis of qPCR expression data examining associations with patient demographics, location, cardiovascular risk factors, and bicuspid vs. tricuspid aortic valve phenotypes, and (4) functional characterization using siRNA-mediated knockdown in primary vascular smooth muscle cells (VSMCs). Results: We identified four lncRNAs as differentially expressed in TAA tissue compared to healthy controls, consistently across bulk and scRNA-seq datasets. Of these, CASC15 and MIR99AHG showed significant overexpression in TAA specimens by qPCR validation (3.1- and 3.2-fold, respectively, both p < 0.001), with scRNA-seq localizing this upregulation to structural cells (log2 FC: 3.7 and 5.3, both p < 0.001). Subsequent qPCR stratification analysis showed that CASC15 expression was higher in the outer vs. inner curvature (1.2-fold, p < 0.05) and decreased in patients with aortic diameters ≥ 52 mm (1.3-fold decrease, p < 0.01). MIR99AHG expression was increased in patients ≥ 50 years (2.0-fold, p < 0.01) and in males vs. females (1.5-fold, p < 0.05). To assess biological relevance, functional analysis in primary VSMCs revealed that specifically CASC15 knockdown caused loss of contractility, increased apoptosis, and reduced proliferation. Conclusion: CASC15 and MIR99AHG show distinct expression patterns in TAA with specific regulatory features. The increased expression of CASC15 in the outer curvature but decreased levels in aneurysms ≥ 52 mm suggest its utility as a biomarker for early TAA detection and progression monitoring. Age- and sex-dependent MIR99AHG expression indicates subgroup-specific pathophysiological mechanisms. The functional impact of CASC15 on VSMC contractility, apoptosis, and proliferation establishes its mechanistic relevance in TAA development. These findings identify lncRNAs as promising targets for risk stratification and clinical applications. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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