Wilms Tumor 1-associated Protein Promotes Sepsis-induced Disseminated Intravascular Coagulation by Stabilizing...

Disseminated intravascular coagulation (DIC) is a life-threatening condition characterized by uncontrolled coagulation and systemic inflammation, often triggered by sepsis. Recent studies highlight the role of N6-methyladenosine (m6A) modification in regulating endothelial dysfunction and coagulation pathways. However, the specific role of Wilms tumor 1-associated protein (WTAP)-a component of the m6A methyltransferase complex-in sepsis-induced DIC remains poorly understood.

HUVECs were stimulated with LPS to establish an in vitro inflammation model. WTAP expression was knocked down using shRNA, and its effects on intercellular adhesion molecule 1 (ICAM1) and tissue factor (TF) expression were analyzed via qPCR, Western blot, and RIP assays. The stability of ICAM1 mRNA was assessed using Actinomycin D treatment. An in vivo sepsis-induced DIC rat model was used to evaluate coagulation parameters, histopathological changes, and WTAP and ICAM1, TF expression in response to WTAP knockdown.

LPS stimulation significantly increased WTAP expression and m6A modification levels in HUVECs, leading to increased ICAM1 expression and enhanced TF activity. WTAP knockdown reduced ICAM1 and TF expression, as well as TF activity. RIP and mRNA stability assays confirmed that WTAP stabilizes ICAM1 mRNA via m6A modification. In the DIC rat model, WTAP knockdown improved coagulation parameters, reduced microthrombus formation in lung and kidney tissues, and inhibited the coagulation cascade.

WTAP stabilizes ICAM1 mRNA via m6A modification, thereby increasing ICAM1 expression and enhancing TF activity in LPS-stimulated HUVECs. Knocking down WTAP in rats improves sepsis-induced DIC.