Abstract Body (Do not enter title and authors here): Background: Influenza A virus (IAV) infection is frequently linked to cardiovascular complications, yet the underlying mechanisms remain unclear. Endothelial cells (ECs) are known to play a crucial role in immune responses during IAV infection. SCF E3 ligase F-box protein complex SCFFBXL19 exhibits anti-inflammatory properties, but its function in the cardiac response to IAV infection remains unexplored.
Methods: We generated EC-specific FBXL19 knock-in (KI) mice using cdh5 promoter and subsequently infected them with IAV. We assessed viral titers, antiviral gene expression, cardiac inflammation, and senescence markers in the heart of mouse.
Results: FBXL19^EC-KI mice exhibited decreased viral titers and IAV matrix protein 1 (M1) levels in the heart, along with increased expression of interferon (IFN)-β, IFN-γ, and RANTES. FBXL19 overexpression preserved phosphorylated interferon regulatory factor 3 (p-IRF3) and IRF3 levels, and mitigated cardiac inflammation, as evidenced by reduction of cytokine levels and infiltration of inflammatory cells. Furthermore, we have discovered for the first time that IAV triggered cardiac senescence, which can be attenuated by EC-specific overexpression of FBXL19.
Conclusions: Endothelial cell-specific overexpression of FBXL19 protects the heart from IAV-induced damage by enhancing antiviral immunity, and suppressing inflammation and cellular senescence. Therefore, targeting FBXL19 may present a therapeutic approach for managing cardiac complications in influenza patients.