期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 909, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174438
关键词
Sodium tanshinone IIA sulfonate; Myocardial dysfunction; Autophagy; NLRP3 inflammasome
资金
- National Science Foundation [81703877, 82074216, 82004135]
- Science and Technology Planning Project of Guangzhou [202102010301]
- Featured Innovative Project from Guangdong Provincial Universities [2019KTSCX029]
- China Association of Chinese Medicine [2019-QNRC2-C06]
- Guangzhou University of Chinese Medicine
- Foundation of Guangdong Province of CM [220211187, 20201142]
- team for the prevention and treatment of acute myocardial infarction with Chinese medicine [2019KCXTD009]
This study demonstrates that STS can increase survival rates in mice, improve compromised cardiac function, reduce myocardial inflammatory injury, and promote autophagy while attenuating NLRP3 inflammasome activation. Additionally, STS may alleviate endotoxemia-induced mortality and cardiomyopathy by promoting autophagy and inhibiting NLRP3 inflammasome overactivation.
Increasing evidence indicates that patients or experimental animals exposure to endotoxin (lipopolysaccharides, LPS) exert deleterious cardiac functions that greatly contribute to morbidity and mortality. The pathophysiologic processes, including NLRP3 inflammasome overactivation and cardiac inflammatory injury, are complicated. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, is a naturally occurring compound extracted from Salvia miltiorrhiza and has anti-inflammatory and cardioprotective properties. In this study we examined the effect of STS on endotoxin-induced cardiomyopathy and investigated the underlying mechanisms. An endotoxemic mouse model was established by injecting LPS (10 mg/kg). Different doses of STS were administered intraperitoneally (5, 10, or 50 mg/kg) at different time points (2/12 h, 4/12 h, and 8/12 h) after LPS challenge to assess its effect on survival of mice with endotoxemia. In parallel, cardiac function, myocardial inflammatory cytokines, cardiomyocyte pyroptosis and autophagy were evaluated to determine the extent of myocardial damage due to sepsis in the presence and absence of STS at the optimal dose (10 mg/kg) and time-point (2/12 h). The results demonstrated that STS increased the survival rates, improved the compromised cardiac function and reduced myocardial inflammatory injury associated with enhanced autophagy and mitigated NLRP3 inflammasome activation. Moreover, inhibiting of autophagy or blocking the AMPK pathway reversed STS-elicited prevention of cardiomyopathy and activated the NLRP3 inflammasome in endotoxemic mice. Collectively, our study demonstrates that STS attenuates endotoxemia-induced mortality and cardiomyopathy, which may be associated with promotion of autophagy and inhibition of NLRP3 inflammasome overactivation.
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