黄芪甲苷通过调节 NOX4/JNK/BAX 通路改善脓毒症诱导的心肌功能障碍。

Astragaloside IV ameliorates sepsis-induced myocardial dysfunction by regulating NOX4/JNK/BAX pathway.

机构信息

Foshan Hospital of Traditional Chinese Medicine, The Eighth Affiliated Hospital of Guangzhou University of Chinese Medicine, Foshan, Guangdong Province, China; The Second Clinical Colledge of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.

The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Province, China; The Second Clinical Colledge of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.

出版信息

Life Sci. 2022 Dec 1;310:121123. doi: 10.1016/j.lfs.2022.121123. Epub 2022 Oct 24.

DOI:10.1016/j.lfs.2022.121123

PMID:36302499

Abstract

AIMS

Sepsis can induce multiple organ dysfunction, and sepsis-induced myocardial dysfunction (SIMD) is relatively common. The current dilemma might ascribe partly to SIMD's lack of unified molecular mechanisms. Our study aims to assess the function of Astragaloside IV (ASI) in cecal ligation and puncture (CLP)-induced cardiac dysfunction and explore its underlying mechanisms.

MAIN METHODS

In vivo, ASI (30 mg/kg/day), NADPH oxidase 4 (NOX4) inhibitor 4-hydroxy-3-methoxyacetophenone (APO, 30 mg/kg/day), reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC, 150 mg/kg/day) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125, 15 mg/kg/day) were severally administered to Sprague Dawley rats following the CLP surgery. The cardiac function, cardiac enzyme markers, proinflammatory cytokine, and cell apoptosis-associated proteins were detected. In vitro, cardiomyocyte H9C2 cells were treated with lipopolysaccharide (LPS, 40 μg/ml) after the presence of ASI (100 μmol/ml), SP600125 (10 μmol/ml), APO (10 μmol/ml). A series of experiments verified the relationship among NOX4, JNK, and BAX.

KEY FINDINGS

The results indicated that CLP-induced sepsis increased the secretion of creatine kinase isoenzymes (CKMB), brain natriuretic peptide (BNP), cardiac troponin T (c-TnI), interleukin-1β (IL-1β) and interleukin-18 (IL-18), as well as the protein expression of NOX4 and Caspase-3 in vivo. LPS increased the protein level of NOX4 and Caspase-3, upregulated the rate of p-JNK/JNK, and downregulated the rate of Bcl2/BAX in vitro. ASI can reverse these changes in vivo and has a synergistic effect with APO and SP600125 in vitro.

SIGNIFICANCE

This study suggested that ASI may ameliorate SIMD, through regulating NOX4/JNK/BAX signaling pathway, which may be a feasible therapeutic strategy.

摘要

目的

脓毒症可导致多器官功能障碍，脓毒症诱导的心肌功能障碍（SIMD）较为常见。目前的困境部分归因于 SIMD 缺乏统一的分子机制。本研究旨在评估黄芪甲苷（ASI）在盲肠结扎和穿刺（CLP）诱导的心脏功能障碍中的作用，并探讨其潜在机制。

主要方法

体内实验中，CLP 手术后，分别给予 Sprague Dawley 大鼠 ASI（30mg/kg/天）、NADPH 氧化酶 4（NOX4）抑制剂 4-羟基-3-甲氧基苯乙酮（APO，30mg/kg/天）、活性氧（ROS）抑制剂 N-乙酰半胱氨酸（NAC，150mg/kg/天）和 c-Jun NH2-末端激酶（JNK）抑制剂（SP600125，15mg/kg/天）。检测心功能、心肌酶标志物、促炎细胞因子和细胞凋亡相关蛋白。体外实验中，用脂多糖（LPS，40μg/ml）处理心肌细胞 H9C2 后，加入 ASI（100μmol/ml）、SP600125（10μmol/ml）、APO（10μmol/ml）。一系列实验验证了 NOX4、JNK 和 BAX 之间的关系。

主要发现

CLP 诱导的脓毒症增加了肌酸激酶同工酶（CKMB）、脑钠肽（BNP）、心肌肌钙蛋白 T（c-TnI）、白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的分泌，以及体内 NOX4 和 Caspase-3 的蛋白表达。LPS 增加了 NOX4 和 Caspase-3 的蛋白水平，上调了 p-JNK/JNK 的比率，下调了 Bcl2/BAX 的比率。ASI 可逆转体内这些变化，并与 APO 和 SP600125 在体外具有协同作用。