LncRNA NR_190073.1 mediates the cardioprotective effect of ulinastatin in sepsis through notch signaling.

Abstract

Sepsis induced myocardial injury (SIMI), a severe complication of sepsis, is characterized by systemic inflammatory dysregulation and impaired cardiac function. Ulinastatin, a broad-spectrum protease inhibitor, has demonstrated therapeutic potential in mitigating sepsis-associated organ injury; however, its specific cardioprotective mechanisms remain incompletely understood. In this study, we employed a lipopolysaccharide-induced SIMI mouse model to investigate the therapeutic effects of ulinastatin. Through transcriptome sequencing and analysis, we identified key molecular targets implicated in SIMI and elucidated the mechanism of action of ulinastatin, with validation at the molecular and cellular levels. Hemodynamic monitoring and echocardiography indicated that ulinastatin significantly improved cardiac function (heart rate, blood pressure, and ECG parameters). Transcriptome sequencing revealed a novel regulatory long non-coding RNA (lncRNA)-NR_190073.1 (at the time of this study, it was initially identified as XR_003954096.2 in the GRCm39 assembly). Histopathological analysis and quantification of inflammatory factors showed that ulinastatin treatment significantly attenuated myocardial inflammation (TNF-&#x3b1; and IL-1&#x3b2;, p&#xa0;<&#xa0;0.05), which was accompanied by a decrease in cardiomyocyte apoptosis as observed in ultrastructural assessments. Mechanistically, western blot and reverse transcription quantitative polymerase chain reaction analyses confirmed that ulinastatin enhances Notch signaling via upregulation of NR_190073.1, modulating NICD and downstream effector Hes1 to alleviate the inflammatory response. Notably, in contrast to direct TLR4 inhibition, the cardioprotective effects of ulinastatin appear to be primarily mediated through Notch-dependent lncRNA regulatory mechanisms. This study delineates an NR_190073.1-mediated therapeutic pathway of ulinastatin, offering a novel target for SIMI treatment exploration.