Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Int J Mol Med. 2019 Oct;44(4):1255-1266. doi: 10.3892/ijmm.2019.4309. Epub 2019 Aug 8.
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 cardiomyoblasts 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 hemodynamic 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 immunosorbent 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.
脓毒症诱导性心功能障碍的主要机制是内皮屏障功能丧失。神经调节蛋白 1（NRG-1）对多个靶标发挥作用。本研究旨在确定 NRG-1 在心肌细胞中的保护作用，包括内皮、抗炎和抗凋亡作用。脂多糖（LPS）诱导脓毒症后，大鼠连续或间断给予载体或重组人 NRG-1（rhNRG-1；10μg/kg/天）1 或 2 天。H9c2 心肌细胞用 LPS（10μg/ml）处理 12 和 24h，同时或不给予 rhNRG-1（1μg/ml）。在脓毒症诱导后 48h 记录存活率。采用血流动力学方法评估心功能，观察心肌形态。采用免疫荧光法检测血管性血友病因子水平。采用酶联免疫吸附试验检测血清肿瘤坏死因子-α、白细胞介素-6、细胞间黏附分子-1 和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。采用末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色法检测细胞凋亡率。采用 Western blot 法检测 Ras 同源家族成员 A（RhoA）和 Rho 相关蛋白激酶 1（ROCK1）蛋白水平。采用透射电镜观察内皮细胞和心肌超微结构变化。结果显示，与假手术组相比，NRG-1 治疗组大鼠心肌损伤程度较轻。NRG-1 给药增强了血管的屏障功能，减少了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。结果表明，NRG-1 通过多种靶点改善心功能，提高脓毒症大鼠的存活率，发挥保护作用。本研究结果为逆转脓毒症中心肌和内皮细胞损伤提供了新的思路。
