MiR-221-5p aggravates sepsis-induced myocardial injury by targeting neuropilin-1.

Abstract

Sepsis-induced cardiac dysfunction is a primary contributor to mortality, and microRNAs (miRNAs) are recognized as crucial mediators in sepsis pathogenesis. This study aims to identify the key regulatory miRNAs involved in cardiac dysfunction stemming from sepsis. We developed a rat model of sepsis using cecal ligation and puncture (CLP). Myocardial tissue from these rats underwent miRNA sequencing and transcriptome sequencing. Echocardiography was utilized to assess heart function, while cardiac damage was evaluated through HE staining, analysis of inflammatory factors, and detection of tissue injury biomarkers. To model inflammation-induced cardiomyocyte injury, rat cardiomyocyte H9C2 cells were treated with lipopolysaccharide (LPS). Cellular viability was determined using CCK8, and apoptosis was assessed via TUNEL staining and flow cytometry. Oxidative stress levels were analyzed by flow cytometry, and related marker levels were quantified by ELISA. Our results demonstrated that the CLP group displayed substantial cardiac dysfunction, myocardial injury, and elevated inflammatory factor levels. MiR-221-5p was found to be upregulated in both the in vivo and in vitro models. Overexpression of miR-221-5p reduced cardiomyocyte survival while increased apoptotic activity and oxidative stress in LPS-stimulated H9C2 cell. Mechanistically, Neuropilin-1 (NRP1) was identified as a target of miR-221-5p. The cardioprotective effect of miR-221-5p inhibition was reversed by NRP1 knockdown. Furthermore, in vivo administration of a miR-221-5p antagomir mitigated cardiac dysfunction and myocardial damage associated with septic conditions. In conclusion, our findings indicate that miR-221-5p exacerbates septic cardiomyopathy by negatively regulating NRP1, suggesting that the miR-221-5p/NRP1 pathway could represent a novel therapeutic strategy for sepsis-related heart complications.