The Role of BMP2/4 in Intestinal Ischemia-Reperfusion Injury: Bridging Smad1/5 and Notch Pathways via Smad6

Background and Aim: Intestinal ischemia-reperfusion (I/R) injury is a significant clinical problem linked to conditions like acute mesenteric ischemia and intestinal obstruction. This study explores the mechanisms of bone morphogenetic proteins (BMPs)-Smads and Notch pathways in I/R injury. Methods: The study employed both in vitro experiments and animal models to analyze the interactions between BMP2/4, the Smad1/5 pathway, and the Notch signaling pathway. Various assays, including western blotting, immunohistochemistry, and RNA sequencing, were utilized to measure molecular and cellular changes. The effects of BMP and Notch pathway inhibitors were also assessed. Specifically, barrier function, cell damage, and inflammatory responses were investigated. Results: Elevated levels of BMP2/4 were observed following intestinal I/R, leading to the activation of the Smad1/5 pathway, which contributed to mucosal barrier damage and increased inflammatory responses. Blocking BMPs or intervening in Notch intracellular domain (NICD), hairy and enhancer of split-1 (HES-1), and Smad6 produced significant regulatory effects on cell damage, inflammatory responses, and barrier function integrity in both in vivo and in vitro models. Conclusions: The findings indicate that BMP2/4 exacerbate intestinal I/R injury through the Smad1/5 pathway, promoting mucosal barrier breakdown and inflammation. The Notch pathway appears to counteract these effects, offering potential therapeutic targets. Further research may focus on developing strategies to modulate these pathways to improve clinical outcomes in intestinal I/R injury.