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异丙酚通过抑制 PPARγ/HMGB1/NLRP3 轴减轻内毒素诱导的心肌细胞损伤,抑制炎症和细胞凋亡。

Propofol ameliorates endotoxin‑induced myocardial cell injury by inhibiting inflammation and apoptosis via the PPARγ/HMGB1/NLRP3 axis.

机构信息

Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China.

出版信息

Mol Med Rep. 2021 Mar;23(3). doi: 10.3892/mmr.2020.11815. Epub 2021 Jan 5.

Abstract

Endotoxin lipopolysaccharide (LPS) is one of the primary causes of myocardial injury. Propofol confers protective effects against LPS‑induced myocardial damage; however, the biological functions and mechanisms underlying propofol are not completely understood. The present study aimed to investigate the effects of propofol on LPS‑induced myocardial injury. Primary neonatal rat cardiomyocytes were treated with LPS to establish a myocardial injury model. LDH release in the culture media was measured using a LDH assay kit. The interactions between NLR family pyrin domain containing 3 (NLRP3), apoptosis‑associated speck‑like protein containing A CARD (ASC) and pro‑caspase‑1 were determined using a co‑immunoprecipitation assay. Cell viability was measured using an MTT assay, and the levels of cell apoptosis were determined using flow cytometry, JC‑1 staining (mitochondrial membrane potential) and caspase‑3 activity assays. The mRNA expression levels of TNF‑α, IL‑6, IL‑1β and IL‑18, and the protein expression levels of NLRP3, ASC, pro‑caspase‑1, caspase‑1 p10, pro‑IL‑1β, IL‑1β, pro‑IL‑18, IL‑18, high mobility group box‑1 (HMGB1) and peroxisome proliferator‑activated receptor γ (PPARγ) were analyzed using reverse transcription‑quantitative PCR and western blotting analyses, respectively. ELISAs were performed to measure the production of inflammatory mediators, including TNF‑α, IL‑6, IL‑1β and IL‑18. The present results demonstrated that pretreatment with propofol significantly attenuated LPS‑induced neonatal rat cardiomyocyte injury in a concentration‑ and time‑dependent manner. Propofol pretreatment also significantly inhibited LPS‑induced cardiomyocyte inflammation and apoptosis. The results suggested that propofol pretreatment inactivated HMGB1‑dependent NLRP3 inflammasome signaling, which involved PPARγ activation. Therefore, the results indicated that propofol reduced endotoxin‑induced cardiomyocyte injury by inhibiting inflammation and apoptosis via the PPARγ/HMGB1/NLRP3 axis, suggesting that propofol may serve as a potential therapeutic agent for septic myocardial damage.

摘要

内毒素脂多糖(LPS)是心肌损伤的主要原因之一。异丙酚对 LPS 诱导的心肌损伤具有保护作用,但异丙酚的生物学功能和机制尚不完全清楚。本研究旨在探讨异丙酚对 LPS 诱导的心肌损伤的影响。用 LPS 处理原代新生大鼠心肌细胞,建立心肌损伤模型。用 LDH 试剂盒测定培养基中 LDH 的释放。用免疫共沉淀法测定 NLR 家族含pyrin 域蛋白 3(NLRP3)、凋亡相关斑点样蛋白含有 A 域(ASC)和前胱天蛋白酶-1 之间的相互作用。用 MTT 法测定细胞活力,用流式细胞术、JC-1 染色(线粒体膜电位)和 caspase-3 活性测定法测定细胞凋亡水平。用逆转录定量 PCR 和 Western blot 分析分别分析 TNF-α、IL-6、IL-1β 和 IL-18 的 mRNA 表达水平以及 NLRP3、ASC、前胱天蛋白酶-1、caspase-1 p10、pro-IL-1β、IL-1β、pro-IL-18、IL-18、高迁移率族蛋白 B1(HMGB1)和过氧化物酶体增殖物激活受体 γ(PPARγ)的蛋白表达水平。用 ELISA 法测定 TNF-α、IL-6、IL-1β 和 IL-18 等炎症介质的产生。结果表明,异丙酚预处理呈浓度和时间依赖性显著减轻 LPS 诱导的新生大鼠心肌细胞损伤。异丙酚预处理还显著抑制 LPS 诱导的心肌细胞炎症和凋亡。结果表明,异丙酚预处理通过激活 PPARγ 抑制 HMGB1 依赖性 NLRP3 炎症小体信号,从而抑制炎症和凋亡。因此,结果表明,异丙酚通过抑制炎症和凋亡减轻内毒素诱导的心肌细胞损伤,通过 PPARγ/HMGB1/NLRP3 轴,提示异丙酚可能是脓毒症心肌损伤的潜在治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c38c/7821353/5faf479fc09b/mmr-23-03-11815-g00.jpg

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