Circular RNA-Cacna1d Plays a Critical Role in Sepsis-induced Lung Injury by Sponging microRNA-185-5p

• Published in: American journal of respiratory cell and molecular biology Vol. 72; no. 2; pp. 181 - 194
• Main Authors: Wang, Jiajia, Gao, Jinhui, Ding, Ling, Yang, Xuanzhe, Zheng, Dong, Zeng, Yuanyuan, Zhu, Jianjie, Lei, Wei, Chen, Cheng, Liu, Zeyi, Huang, Jian-an
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.02.2025
• Subjects: Animals; Biomarkers; Circular RNA; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Female; Humans; Inflammation; Lung - metabolism; Lung - pathology; Lung diseases; Lung Injury - etiology; Lung Injury - genetics; Lung Injury - metabolism; Lung Injury - pathology; Lungs; Male; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Microvasculature; miRNA; Molecular modelling; Next-generation sequencing; Peripheral blood; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; RNA, Circular - genetics; RNA, Circular - metabolism; Sepsis; Sepsis - complications; Sepsis - genetics; Signal Transduction; Therapeutic targets; ROCK1; RhoA; circRNA-Cacna1d; miRNA-185-5p; sepsis
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2024-0067OC

The role of circular RNAs (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 patients with sepsis. 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 qRT-PCR, and its biological function in sepsis-induced lung injury was validated and . The interactions among circRNA-Cacna1d, microRNAs (miRNAs), and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from patients with sepsis was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of mice with sepsis and in microvascular endothelial cells after 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 mice with sepsis. 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 control subjects. Higher levels of circRNA-Cacna1d in patients with sepsis 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 a miRNA-185-5p sponge. circRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.