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

Background: Septic myocardial injury is one of the most life-threatening organ dysfunction. The gamma-secretase-based approaches have been developed as potential strategies for diverse diseases management. Unfortunately, the role of gamma-secretase inhibitor in septic myocardial injury is unclarified. The present study aims to investigate the effect of gamma-secretase inhibitor in septic myocardial injury and reveal its mechanism. Methods: The mouse model of septic myocardial injury was established by intraperitoneally injection of lipopolysaccharide (LPS), and gamma-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. Results: LPS 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 gamma-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)-1 beta and tumor necrosis factor-alpha (TNF-alpha) 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 gamma-secretase inhibitor-treated myocardial cells. Conclusion: The results demonstrate that gamma-secretase inhibitor alleviates septic myocardial injury via activating JAK2/STAT3 signaling, and provide novel therapeutic direction for septic myocardial injury.