Sacubitril/valsartan (LCZ696) reduces myocardial injury following myocardial infarction by inhibiting NLRP3‑induced pyroptosis via the TAK1/JNK signaling pathway

Autor: Jian-Fen Shen, Zhongbao Fan, Guang Sun, Guoxian Qi
Rok vydání: 2021
Předmět:
Male
Cancer Research
Cardiotonic Agents
Inflammasomes
Myocardial Infarction
Pharmacology
Biochemistry
Sacubitril
Cell Line
Rats
Sprague-Dawley
NLR Family
Pyrin Domain-Containing 3 Protein
Pyroptosis
Genetics
medicine
Animals
LCZ696
Myocytes
Cardiac
Ventricular remodeling
Molecular Biology
Inflammation
business.industry
Aminobutyrates
Biphenyl Compounds
Intracellular Signaling Peptides and Proteins
JNK Mitogen-Activated Protein Kinases
Inflammasome
Articles
Phosphate-Binding Proteins
MAP Kinase Kinase Kinases
medicine.disease
NLRP3 inflammasome
Disease Models
Animal
Drug Combinations
Heart Injuries
Oncology
Apoptosis
Caspases
TAK1/JNK signaling pathway
Cytokines
Valsartan
Molecular Medicine
Myocardial fibrosis
Reactive Oxygen Species
business
Sacubitril
Valsartan
Signal Transduction
medicine.drug
Transforming growth factor
Zdroj: Molecular Medicine Reports
ISSN: 1791-3004
1791-2997
Popis: The present study aimed to investigate the protective effects of sacubitril/valsartan (LCZ696) on ventricular remodeling in myocardial infarction (MI) and the effects of the inflammasome-mediated inflammatory response. First, a rat model was established. Animals were then treated with LCZ696 so that the histopathological changes associated with ventricular remodeling could be investigated. The serum levels of the inflammatory factors IL-18 and IL-1β were also determined by ELISA. Immunofluorescence was used to investigate the ratio of pyroptosis following MI modelling. Western blotting and reverse transcription-quantitative PCR were used to detect the relative expression levels of proteins and mRNAs in the transforming growth factor β-activated kinase-1 (TAK1)/JNK pathway and those associated with the NLR pyrin family domain containing 3 (NLRP3) inflammasome, respectively. The present study also investigated the regulatory mechanisms and associations between the TAK1 and JNK pathways, NOD-, leucine-rich repeat- and the NLRP3 inflammasome, in H9C2 cells and myocardial cells from the rat model of MI. LCZ696 improved MI-induced myocardial fibrosis, rescued myocardial injury and suppressed the release of inflammatory factors. With regards to myocardial cell damage, pyroptosis in cardiomyocytes was observed. The in vitro experiments demonstrated that the overexpression of TAK1 promoted lysis of the N-terminal of GSDMD, thereby activating the NLRP3 inflammasome and promoting the conversion of pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, respectively. In contrast, the silencing of TAK1 inhibited the expression levels of the NLRP3 inflammasome. In summary, LCZ696 reduced the expression levels of the NLRP3 inflammasome, suppressed inflammatory responses, improved the ventricular remodeling and exhibited protective effects in the MI heart by inhibiting the TAK1/JNK signaling pathway.
Databáze: OpenAIRE
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