CircRNA-Cacna1d Plays a Critical Role in Sepsis-induced Lung Injury by Sponging miRNA-185-5p.

ABSTRACT

The role of circRNAs in sepsis-induced lung injury is not clear. This study investigated the role and molecular mechanism of a novel circRNA in sepsis-induced lung injury and explored its prognostic value in sepsis patients. In this study, aberrant circRNA expression profiling in lung tissues from mice with sepsis-induced lung injury was analyzed using high-throughput sequencing. CircRNA-Cacna1d was verified by quantitative real-time polymerase chain reaction, and its biological function in sepsis-induced lung injury was validated in vitro and in vivo. The interactions among circRNA-Cacna1d, miRNAs, and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from sepsis patients was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of sepsis mice and microvascular endothelial cells after lipopolysaccharide (LPS) challenge. CircRNA-Cacna1d knockdown alleviated inflammatory response and ameliorated the permeability of vascular endothelium, thereby mitigating sepsis-induced lung injury and significantly improving the survival rate of sepsis mice. Mechanistically, circRNA-Cacna1d directly interacted with miRNA-185-5p and functioned as a miRNA sponge to regulate the RhoA/ROCK1 signaling pathway. The expression level of circRNA-Cacna1d in patients with early sepsis was significantly higher than that in the healthy controls. Higher levels of circRNA-Cacna1d in sepsis patients were associated with increased disease severity and poorer outcomes. In conclusions, circRNA-Cacna1d may play a role in sepsis-induced lung injury by regulating the RhoA/ROCK1 axis by acting as miRNA-185-5p sponge. CircRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.