Abstract Background and objective: Aortic dissection (AD) is a fatal disease of which molecular pathogenesis remains unelucidated. Inflammatory responses have been reported to play an important role in AD development in mice. We found that spleen tyrosine kinase, which is involved in various inflammatory pathways, was activated in mouse AD tissue. However, role of Syk in AD pathogenesis is unknown. Method and result: The mouse AD model was created by continuous infusion of beta-aminopropionitrile and angiotensin II for 14 days. Systemic Syk inhibition with oral fostamatinib administration significantly increased AD mortality (p=0.0138) and AD lesion length (p=0.0123) compared to control group. Immunofluorescent study confirmed Syk activation both in adventitial macrophages and medial smooth muscle cells in mouse AD tissue. To clarify role of syk in macrophage or smooth muscle cells, we generated macrophage- and smooth muscle cell-specific Syk deleted mice using the Cre-LoxP system and Cre-ERT2 system (mfSyk-KO, smSyk-KO, respectively). mfSyk-KO revealed no significant differences in mortality (p=0.7481) and lesion length (p=0.9893) of AD compared to littermate control. On the other hand, smSyk-KO exhibited a higher mortality than the control group (p=0.0552). Although lesion length was not significantly different between the two groups, when analyzed using cutoff values (entire aorta: cutoff 20 mm, p=0.0460; descending thoracic region: cutoff 10 mm, p=0.0356), smSyk-KO mice developed significantly longer lesions than control mice. Analysis of the transcriptome showed that the stimulation of AD increased the expression of genes involved in cell proliferation and cell migration caused by inflammation. This result is consistent with what is known so far. Also, we found that Syk suppress immune mechanisms against inflammation in healthy aortic tissue before the stimulation of AD. Aortic tissue with a specific Syk knockout in smooth muscle cells showed significant changes in expression of genes associated with the extracellular matrix caused by stimulation of AD. Conclusion and consideration: Syk in SMC have protective role in pathogenesis of AD. And, it was also suggested that the extracellular matrix is involved in the mechanism. In the future, we plan to perform Western blotting to investigate changes in Syk and inflammatory proteins over time and tissue staining related extracellular matrix. These will give more detailed facts about the mechanisms of AD.
Shibata et al. (Sat,) studied this question.