γ‐Secretase inhibitor alleviates lipopolysaccharide‐induced myocardial injury through regulating JAK2/STAT3 signaling

Abstract

AbstractBackgroundSeptic myocardial injury is one of the most life‐threatening organ dysfunction. The γ‐secretase‐based approaches have been developed as potential strategies for diverse diseases management. Unfortunately, the role of γ‐secretase inhibitor in septic myocardial injury is unclarified. The present study aims to investigate the effect of γ‐secretase inhibitor in septic myocardial injury and reveal its mechanism.MethodsThe mouse model of septic myocardial injury was established by intraperitoneally injection of lipopolysaccharide (LPS), and γ‐secretase inhibitor MW167 was applied in this model. RNA‐sequencing analysis and further bioinformatics analyses were used to screen differential expressed genes (DEGs) and potentially enriched pathways between LPS and LPS + MW167 mice. Pathological examination was performed using haematoxylin and eosin (HE) staining. SD‐1029 was used to block JAK2/STAT3 signaling in H9C2 cells and western blot analysis quantified JAK2/STAT3‐related proteins.ResultsLPS induced myocardial injury accompanied with significant inflammatory infiltration and more apoptotic cells. Transcriptome sequencing screened 36 DEGs and bioinformatics identified JAK2/STAT3 signaling pathway was significantly enriched. Further in vitro experiments showed that γ‐secretase inhibitor MW167 activated JAK2/STAT3 pathway. Additionally, MW167 restored cell viability, decreased myocardial injury markers including cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), inhibited pro‐inflammatory cytokines such as interleukin (IL)‐1β and tumor necrosis factor‐α (TNF‐α) and reduced nitric oxide (NO), cyclooxygenase‐2 (COX2) and inducible nitric oxide synthase (iNOS) release. Application of SD‐1029 reversely deteriorated LPS‐induced myocardial injury and inflammatory response in γ‐secretase inhibitor‐treated myocardial cells.ConclusionThe results demonstrate that γ‐secretase inhibitor alleviates septic myocardial injury via activating JAK2/STAT3 signaling, and provide novel therapeutic direction for septic myocardial injury.