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

Shen,Jianfen; Fan,Zhongbao; Sun,Guang; Qi,Guoxian

doi:10.3892/mmr.2021.12315

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

Authors:
- Jianfen Shen
- Zhongbao Fan
- Guang Sun
- Guoxian Qi
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Affiliations: Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Hepatobiliary Surgery, People's Hospital of China Medical University, Liaoning Provincial People's Hospital, Shenyang, Liaoning 110016, P.R. China, Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: July 23, 2021 https://doi.org/10.3892/mmr.2021.12315
Article Number: 676
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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