Department of Cardiology, The First Affiliated Hospital of China Medical University, Heping, 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.
Mol Med Rep. 2021 Sep;24(3). doi: 10.3892/mmr.2021.12315. Epub 2021 Jul 23.
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 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.
本研究旨在探讨沙库巴曲缬沙坦（LCZ696）对心肌梗死（MI）心室重构的保护作用，以及炎症小体介导的炎症反应的影响。首先建立了大鼠模型，然后用 LCZ696 处理动物，以研究与心室重构相关的组织病理学变化。通过 ELISA 法测定血清中炎症因子白细胞介素 18（IL-18）和白细胞介素 1β（IL-1β）的水平。免疫荧光法检测 MI 模型建立后细胞焦亡的比例。Western blot 和逆转录-定量 PCR 法分别检测转化生长因子-β激活激酶 1（TAK1）/c-Jun 氨基末端激酶（JNK）通路相关蛋白和 mRNAs 以及含 NOD 样受体热蛋白结构域蛋白 3（NLRP3）炎症小体的相对表达水平。本研究还探讨了 TAK1 和 JNK 通路、NOD 样受体、富含亮氨酸重复序列和 NLRP3 炎症小体在 H9C2 细胞和 MI 大鼠心肌细胞中的调控机制及其相关性。LCZ696 改善了 MI 引起的心肌纤维化，挽救了心肌损伤并抑制了炎症因子的释放。在心肌细胞损伤方面，观察到心肌细胞焦亡。实验表明，TAK1 的过表达促进 GSDMD N 端的裂解，从而激活 NLRP3 炎症小体，促进前白细胞介素 1β（pro-IL-1β）和前白细胞介素 18（pro-IL-18）分别转化为成熟的白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）。相反，TAK1 的沉默抑制了 NLRP3 炎症小体的表达水平。综上所述，LCZ696 通过抑制 TAK1/JNK 信号通路，降低 NLRP3 炎症小体的表达水平，抑制炎症反应，改善 MI 心脏的心室重构，发挥保护作用。
