Prevention of endotoxin-induced cardiomyopathy using sodium tanshinone IIA sulfonate: Involvement of augmented autophagy and NLRP3 inflammasome suppression.

Abstract

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.

• Authors: Peipei Chen, Qiyuan An, Yuxin Huang, Minzhou Zhang, Shuai Mao
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 909 Pg. 174438 (Oct 15 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 34437885 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Endotoxins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Phenanthrenes
• tanshinone II A sodium sulfonate

Topics

• Animals
• Autophagy (drug effects, immunology)
• Cardiomyopathies (diagnosis, immunology, microbiology, prevention & control)
• Disease Models, Animal
• Echocardiography
• Endotoxemia (complications, drug therapy, immunology, microbiology)
• Endotoxins (blood, immunology)
• Heart Ventricles (diagnostic imaging, drug effects, immunology, pathology)
• Humans
• Inflammasomes (antagonists & inhibitors, immunology, metabolism)
• Male
• Mice
• Myocytes, Cardiac
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, metabolism)
• Phenanthrenes (pharmacology, therapeutic use)
• Pyroptosis (drug effects, immunology)