P6493Syk activation is a defense mechanism in murine model of aortic dissection

Abstract

Abstract Background Aortic dissection (AD) is a serious clinical condition with unknown etiology that frequently results in fatal outcome. Recent studies showed essential role of inflammatory response both in promoting AD and aortic aneurysm (AA). However, the difference of the molecular pathogenesis between AD and AA is unclear. Previously, we reported that Syk, a tyrosine kinase that regulates differentiation and activation of inflammatory cells, promotes AA formation in a mouse model. Objective In the current study, we investigated the role of Syk in AD. Methods and results A mouse AD model was created by continuous infusion of beta-aminopropionitrile (125 mg/kg/day) and angiotensin II (1,000 ng/min/kg) (BAPN+AngII), which caused AD in approximately 80% of mice within 14 days. Immunohistochemical staining for activated (phosphorylated) Syk (pSyk) revealed that Syk was inactive in normal mouse aorta, but was activated in the aortic walls after AD development. Double immunofluorescence staining for pSyk and smooth muscle alpha actin showed that Syk was active not only in the infiltrating inflammatory cells, but also in smooth muscle cells in AD tissue. Western blot analysis revealed that BAPN+AngII treatment caused Syk activation at 3 days before AD development, followed by transient suppression, and reactivation at 14 days after AD development. We examined the significance of Syk activation in AD by treating mice with fostamatinib, a specific Syk inhibitor, before and during BAPN+AngII infusion. Notably, fostamatinib-treated group developed more severe AD compared to the vehicle-treated group. The AD lesion length was 3.80±0.86 mm for vehicle group and 8.87±1.69 mm for fostamatinib group (P<0.05, n=12 for each group). In addition, fostamatinib significantly worsened the mortality of mice due to the rupture of the aorta from 0% to 42% (P<0.05, n=12 for each group). Transcriptome analysis revealed that fostamatinib suppressed both positive and negative regulators of immune response, defense response and inflammatory response. Conclusions These findings uncovered the previously unrecognized role of Syk for protecting the aortic tissue in AD pathogenesis, and suggested fundamentally different disease mechanisms of AD and AA.