Extracellular RNA as a molecular driver and therapeutic target in abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, matrix degradation and smooth muscle cell (SMC) loss, leading to vessel dilation and rupture, with no current pharmaceutical management options. Since recent studies have highlighted the role of extracellular (ex) nucleic acids in promoting inflammation and tissue damage in cardiovascular conditions, we aimed to characterize the contribution of exDNA and exRNA to AAA pathogenesis and evaluate their potential as therapeutic targets in established disease. Circulating exDNA was elevated in patients and mouse models, while plasma levels of exRNA were not associated with AAA development. When RNase A or DNase I was administered to mice with established disease, the targeted degradation of exRNA, but not exDNA, significantly attenuated aneurysm growth. The RNase A treatment produced systemic anti-inflammatory effects (reduced monocyte/granulocyte count) and showed the potential to improve local vascular conditions by preserving SMC integrity, reducing macrophage infiltration and protease expression. These effects were not observed in DNase I-treated animals. In conclusion, while circulating exDNA showed AAA biomarker potential, targeting exRNA by systemic RNase A treatment effectively mitigated aneurysm progression in established disease through pleiotropic modulation of inflammation and tissue remodeling, presenting a novel and promising therapeutic strategy.