Neuregulin-1 protects cardiac function in septic rats through multiple targets based on endothelial cells
Neuregulin-1 protects cardiac function in septic rats through multiple targets based on endothelial cells
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Neuregulin-1通过基于内皮细胞的多靶点保护脓毒症大鼠的心脏功能
DOI：
10.3892/ijmm.2019.4309
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发表时间：
2019-10-01
影响因子：
5.4
通讯作者：
Wang, Xin
中科院分区：
文献类型：
--
作者：
Kang, Wen;Cheng, Yue;Wang, Xin
脓毒症引起的心脏功能障碍的主要机制是内皮屏障功能丧失。 Neuregulin-1 (NRG-1) 在多个靶点上发挥其功能。本研究旨在确定NRG-1对心肌细胞的保护作用，包括内皮、抗炎和抗凋亡作用。脂多糖 (LPS) 诱导的败血症后，给大鼠施用载体或重组人 NRG-1（rhNRG-1；10 µg/kg/天）一到两天。 H9c2 心肌成肌细胞在有或没有 rhNRG-1 (1 µg/ml) 的情况下接受 LPS (10 µg/ml) 处理 12 和 24 小时。脓毒症诱导后 48 小时记录存活率。采用血流动力学方法评价心功能，观察心肌形态。使用免疫荧光测定法检测血管性血友病因子水平。采用酶联免疫吸附法检测血清肿瘤坏死因子α、白细胞介素6、细胞间细胞粘附分子1、血管内皮生长因子水平；采用还原酶法检测血清一氧化氮水平。使用末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色测定细胞凋亡率。使用蛋白质印迹法评估 Ras 同源物家族成员 A (RhoA) 和 Rho 相关蛋白激酶 1 (ROCK1) 的蛋白水平。采用透射电镜观察内皮细胞和心肌超微结构的变化。结果显示，与假手术大鼠相比，NRG-1 治疗的大鼠表现出较少的心肌损伤。 NRG-1 给药可增强脉管系统的屏障功能，减少内皮相关生物标志物的分泌，并发挥抗炎和抗凋亡作用。此外，NRG-1 抑制 RhoA 和 ROCK1 信号传导。结果表明，NRG-1可以改善心脏功能，提高脓毒症大鼠的存活率，并通过全身多个靶点发挥保护作用。目前的结果有助于开发一种逆转脓毒症期间心肌和内皮细胞损伤的新方法。
The primary mechanism underlying sepsis-induced cardiac dysfunction is loss of endothelial barrier function. Neuregulin-1 (NRG-1) exerts its functions on multiple targets. The present study aimed to identify the protective effects of NRG-1 in myocardial cells, including endothelial, anti-inflammatory and anti-apoptotic effects. Subsequent to lipopolysaccharide (LPS)-induced sepsis, rats were administered with either a vehicle or recombinant human NRG-1 (rhNRG-1; 10 µg/kg/day) for one or two days. H9c2 cardio-myoblasts were subjected to LPS (10 µg/ml) treatment for 12 and 24 h with or without rhNRG-1 (1 µg/ml). Survival rates were recorded at 48 h following sepsis induction. The hemo-dynamic method was performed to evaluate cardiac function, and myocardial morphology was observed. Von Willebrand Factor levels were detected using an immunofluorescence assay. Serum levels of tumor necrosis factor α, interleukin-6, intercellular cell adhesion molecule-1 and vascular endothelial growth factor were detected using an enzyme-linked immuno-sorbent assay; the reductase method was performed to detect serum nitric oxide levels. Apoptosis rates were determined using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Ras homolog family member A (RhoA) and Rho-associated protein kinase 1 (ROCK1) protein levels were assessed using western blotting. Transmission electron microscopy was used to observe endothelial cells and myocardial ultrastructure changes. Results revealed that NRG-1-treated rats displayed less myocardial damage compared with sham rats. NRG-1 administration strengthened the barrier function of the vasculature, reduced the secretion of endothelial-associated biomarkers and exerted anti-inflammatory and anti-apoptotic effects. In addition, NRG-1 inhibited RhoA and ROCK1 signaling. The results revealed that NRG-1 improves cardiac function, increases the survival rate of septic rats and exerts protective effects via multiple targets throughout the body. The present results contribute to the development of a novel approach to reverse damage to myocardial and endothelial cells during sepsis.