Aspirin Inhibits the cGAS-STING Signaling Pathway to Ameliorate the Development of Aortic Aneurysm and Dissection

Aortic aneurysm and dissection (AAD) is a life-threatening vascular disease that currently lacks effective pharmacological therapies. Clinical evidences suggest that aspirin may exert a protective effect on AAD, but the underlying molecular mechanism is still unclear at present.

Three mouse animal models of AAD and H₂O₂-induced ferroptosis model in human aortic vascular smooth muscle cells were established. On this basis, RNA sequencing was performed to investigate potential molecular mechanisms, and further experiments were conducted using STING (stimulator of interferon genes) agonist to confirm the mechanisms.

Aspirin was found to ameliorate the progression of AAD in the β-aminopropionitrile and CaPO₄ mouse models. Interestingly, aspirin reduced mortality in mice but did not reduce the incidence of AAD in the β-aminopropionitrile + angiotensin II model. Furthermore, aspirin inhibited H₂O₂-induced ferroptosis in human aortic vascular smooth muscle cells and suppressed activation of cGAS (cyclic GMP-AMP synthase)-STING signaling pathway. Activation of STING with STING agonist markedly increased STING, TBK1 (TANK-binding kinase 1), and IRF3 (interferon regulatory factor 3) phosphorylation and abolished the protective effect of aspirin against H₂O₂-induced ferroptosis in human aortic vascular smooth muscle cells. Western blot and immunofluorescence results indicated significant activation of the cGAS-STING signaling pathway following treatment with STING agonist. Coimmunoprecipitation analysis revealed that cGAS acetylation was considerably enhanced in human aortic vascular smooth muscle cells after aspirin treatment. Additionally, administration of aspirin and dimeric amidobenzimidazole compound 3 showed that dimeric amidobenzimidazole abolished the protective effect of aspirin in the CaPO₄ model. Coimmunoprecipitation results indicated that aspirin promoted cGAS acetylation in mouse aortic tissue. Western blot and immunohistochemistry results also confirmed that the dimeric amidobenzimidazole compound 3 activated phosphorylation of STING, TBK1, and IRF3 and significantly negatively regulated the expression of GPX4. In the β-aminopropionitrile model, dimeric amidobenzimidazole also abolished the protective effect of aspirin.

Aspirin confers a protective effect against AAD by promoting cGAS acetylation and inhibiting the cGAS-STING signaling pathway and ferroptosis in VSMC.