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Gypenoside XLIX targets SIRT1 to block YAP-NLRP3 activation and improve sepsis-induced cardiomyopathy
Wei Zhang1, Wenting Zhu2, Xiao Liu2
1Department of Vascular Surgery, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222005, China; Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
Background:
The pathogenesis of sepsis-induced cardiomyopathy (SIC) remains unclear, presenting a complex challenge in both clinical practice and research. Gypenoside XLIX (Gyp-XLIX) has garnered significant attention for its anti-inflammatory, antioxidant, and various other pharmacological activities; however, its protective effect on SIC has not been thoroughly investigated.
Purpose:
This study aims to explore the effect of Gyp-XLIX on SIC and its potential therapeutic mechanisms.
Methods:
A sepsis mouse model was established through cecal ligation and puncture surgery and treated with Gyp-XLIX. The modeling was evaluated through sepsis model scoring, survival analysis, weight changes, wet-to-dry weight ratio, H&E staining, biochemical assays and cardiac ultrasound. The mechanism exploration was deteced using proteomics sequencing, Western blotting, qPCR, biochemical analysis, and reactive oxygen species assays. Additionally, target proteins of Gyp-XLIX were identified through LC-MS/MS proteomics analysis, molecular docking, CESTA, DARTS, SPR with SIRT1 being a primary focus. Bioinformatics and Immunoprecipitation mass spectrometry analysis, and immunohistochemistry were employed to further elucidate the downstream target of SIRT1, specifically the YAP-NLRP3 pathway. The degradation mechanisms of YAP-NLRP3 were explored using MG132, chloroquine, cycloheximide, and co-immunoprecipitation. Corresponding rescue experiments were conducted in H9C2 cells for further validation.
Results:
Gyp-XLIX effectively mitigates SIC, reduces cardiac inflammation, and restores cardiac structural, left ventricular functional abnormalities, and oxidative stress balance. Proteomics results showed that Gyp-XLIX binded to SIRT1 and alleviates inflammation and oxidative stress. Whereas, SIRT1 is low expressed and alleviated oxidative stress and NLRP3 inflammasome activation in SIC. Mechanically, Gyp-XLIX binded to SIRT1 improved its stability and promoted the deacetylation and phosphorylation of downstream YAP, which in turn regulated YAP degradation. This process subsequently affects the ubiquitination of NLRP3, downstream of YAP, at the K27 site, leading to its degradation and, consequently, alleviating inflammation and oxidative stress during SIC.
Conclusion:
Gyp-XLIX targets SIRT1 to block YAP-NLRP3 activation and improve SIC, suggesting that Gyp-XLIX is an effective protective agent against SIC and represents a promising therapeutic strategy.
