Abstract 16322: Role of Spleen Tyrosine Kinase in Pathomechanism of Aortic Dissection

• Published in: Circulation Vol. 148; no. Suppl_1; p. A16322
• Main Author: SHIBATA, RYO
• Format: Journal Article
• Language: English; Japanese
• Published: Hagerstown, MD Ovid Technologies (Wolters Kluwer Health) 07.11.2023; Lippincott Williams & Wilkins
• Subjects: Smooth muscle; Inflammation; Aortic Dissection
• DOI: 10.1161/circ.148.suppl_1.16322
• ISSN: 0009-7322

Background: Aortic dissection (AD) is a fatal aortic disease of which molecular pathogenesis has not been elucidated. In our previous studies, we found that systemic inhibition of Syk, spleen tyrosine kinase, exacerbates AD leading and sudden death in model mice. However, cell type-specific role of the AD pathogenesis is unknown. Subject: How does Syk contribute to the pathogenesis of AD. And what cells in the aorta contribute to the pathogenesis of AD. Methods and results: Mouse AD model was created by continuous infusion of β-aminopropionitrile and angiotensin II (BAPN+AngII) for 14 days as previously reported. Iba1 and αSMA, markers of activated macrophage (Mϕ) and smooth muscle cell (Sm), respectively, were double-stained with p-Syk in the mouse AD model. As a results, we found that both Mϕ and Sm are activated in the same region as Syk. This suggests that Syk contributes in some way to Mϕ and Sm in the pathogenesis of AD. Mϕ-specific Syk knockout mice were generated using the Cre-LoxP system. Phenotype effects were compared in the controls and Mϕ-specific Syk knockout groups, but there were no significant differences in AD lesion length and mortality. Sm-specific Syk knockout mice were generated using the tamoxifen-induced CreERT2 system to avoid alteration of aortic phenotypic at the baseline. Ten-week-old mice with loxP sequences at both ends of the Syk gene in Sm were injected with 1 mg/day of tamoxifen for 5 days, and In Situ Hybridization showed that p-Syk was reduced in the aortic tunica media after 2 weeks. Phenotypic comparisons with controls what did not receive tamoxifen showed no significant differences in AD lesion length and mortality. These results differ from previous findings that systemic Syk inhibition increases AD. Conclusions: We found that systemic inhibition of Syk exacerbates the pathogenesis and mortality of AD, and that Syk has some activation in Mϕ and Sm. However, deletion of Syk in Mϕ or Sm alone had no apparent effect on the pathogenesis of AD. These results suggest that the action of Syk in AD pathogenesis is not solely due to Mϕ and Sm, but is due to a more complex mechanism involving multiple cells interactions.