GYY4137 ameliorates sepsis-induced cardiomyopathy via NLRP3 pathway

Tao Zhou; Huitao Qian; Nan Zheng; Qiulun Lu; Yi Han

doi:10.1016/j.bbadis.2022.166497

GYY4137 ameliorates sepsis-induced cardiomyopathy via NLRP3 pathway

Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166497. doi: 10.1016/j.bbadis.2022.166497. Epub 2022 Jul 20.

Authors

Tao Zhou¹, Huitao Qian¹, Nan Zheng¹, Qiulun Lu², Yi Han³

Affiliations

¹ Department of Critical Care Medicine, Geriatric ICU, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China.
² Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: qiulunlu@njmu.edu.cn.
³ Department of Critical Care Medicine, Geriatric ICU, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China. Electronic address: hanyi@jsph.org.cn.

PMID: 35868482
DOI: 10.1016/j.bbadis.2022.166497

Abstract

Sepsis-induced cardiomyopathy (SICM) has a poor prognosis, with no effective therapeutic strategy currently. This study aimed to explore the mechanism underlying SICM and investigate the protective role of the hydrogen sulfide (H₂S) donor GYY4137. This study included patients with SICM and animal models of SICM with wild-type and Nlrp3^-/- mice, which were treated with or without GYY4137. Echocardiography, ELISA, TUNEL staining, and immunofluorescence were used to investigate phenotypic alterations. Serum levels of H₂S and cytokines were measured. Inflammatory cell infiltration in the myocardial tissue was identified using immunohistochemistry and immunofluorescence. RNA expression profiles were identified using RNA sequencing. The protective mechanism of GYY4137 was further validated in the crosstalk between macrophages and cardiomyocytes using immunoblotting, real-time polymerase chain reaction (RT-PCR), and immunofluorescence when conditional medium of macrophages boosted by LPS were co-cultured with cardiomyocytes. Patients and animal models of SICM presented with lower serum H₂S levels and heart dysfunction. GYY4137 reduced macrophage infiltration in septic heart tissue. GO analysis suggested that GYY4137 was involved in the inflammatory process. GYY4137 inhibited NLRP3 inflammasome activity in macrophages, reduced the secretion of inflammatory factors, and decreased the production of reactive oxygen species (ROS) in cardiomyocytes, thus exerting protective effects against SICM. We further found that the protective effects of GYY4137 were absent in Nlrp3-knockout models. GYY4137 ameliorates myocardial injury in SICM via the NLRP3 pathway by inhibiting the inflammatory response and reducing the production of myocardial ROS.

Keywords: Hydrogen sulfide; Macrophage; NLRP3 inflammasome; Reactive oxygen species; Sepsis-induced cardiomyopathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiomyopathies* / metabolism
Cytokines / metabolism
Hydrogen Sulfide* / metabolism
Hydrogen Sulfide* / pharmacology
Inflammasomes / metabolism
Lipopolysaccharides / metabolism
Mice
Morpholines
Myocytes, Cardiac / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Organothiophosphorus Compounds
RNA / metabolism
Reactive Oxygen Species / metabolism
Sepsis* / complications
Sepsis* / drug therapy
Sepsis* / metabolism

Substances

Cytokines
GYY 4137
Inflammasomes
Lipopolysaccharides
Morpholines
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Organothiophosphorus Compounds
Reactive Oxygen Species
RNA
Hydrogen Sulfide