Wang Rijun, Wang Ning, Han Yuping, Xu Jiyao, Xu Zesheng
Department of Cardiology, Cangzhou Central Hospital Affiliated of Tianjin Medical University, Cangzhou, Hebei 061014, China.
Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 030024, China.
ACS Omega. 2021 Mar 18;6(12):8271-8278. doi: 10.1021/acsomega.0c06326. eCollection 2021 Mar 30.
Sepsis is a severe infection-induced disease with multiple organ failure, and sepsis-induced cardiomyopathy is a fatal condition. Inflammatory response and oxidative stress are reported to be involved in the development of sepsis-induced cardiomyopathy. Dulaglutide is a novel antidiabetic agent that is currently reported to exert an anti-inflammatory effect. The present study aims to explore the potential protective property of dulaglutide on lipopolysaccharide (LPS)-induced injury on cardiomyocytes.
LPS was used to induce an injury model on cardiomyocytes. The mitochondrial reactive oxygen species (ROS) level was detected using MitoSOX red, and reduced glutathione (GSH) was measured to evaluate the status of oxidative stress in H9c2 myocardial cells. The expressions of NADPH oxidase-1 (NOX-1) and inducible nitric oxidesynthase (iNOS) were determined using real-time PCR and western blot analysis. Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were both used to detect the expressions and concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-17, matrix metalloproteinase-2, and matrix metalloproteinase-9 in H9c2 myocardial cells, respectively. The production of nitric oxide (NO) was measured using the Griess reagent. The levels of creatine kinase isoenzyme-MB (CK-MB) and cardiac troponin I (cTnI) were detected using ELISA. Western blot was utilized to determine the expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p-NF-κB p65 in H9c2 myocardial cells in the nucleus.
First, dulaglutide ameliorated LPS-induced oxidative stress by suppressing the production of mitochondrial ROS and elevating the level of reduced GSH, as well as downregulating NOX-1. Second, the LPS-induced cardiomyocyte injury was alleviated by dulaglutide through downregulating CK-MB and cTnI, accompanied by inhibiting iNOS expression and NO production. Lastly, the production of inflammatory factors and upregulation of MMPs induced by LPS were both significantly reversed by dulaglutide through suppressing the TLR4/Myd88/NF-κB signaling pathway.
Dulaglutide alleviated LPS-induced injury in cardiomyocytes by inhibiting inflammation and oxidative stress.
脓毒症是一种由严重感染引发的伴有多器官功能衰竭的疾病，脓毒症诱导的心肌病是一种致命病症。据报道，炎症反应和氧化应激参与了脓毒症诱导的心肌病的发展过程。度拉糖肽是一种新型抗糖尿病药物，目前有报道称其具有抗炎作用。本研究旨在探讨度拉糖肽对脂多糖（LPS）诱导的心肌细胞损伤的潜在保护作用。
使用LPS诱导心肌细胞损伤模型。使用MitoSOX red检测线粒体活性氧（ROS）水平，并测定还原型谷胱甘肽（GSH）以评估H9c2心肌细胞中的氧化应激状态。使用实时PCR和蛋白质印迹分析确定NADPH氧化酶-1（NOX-1）和诱导型一氧化氮合酶（iNOS）的表达。实时PCR和酶联免疫吸附测定（ELISA）分别用于检测H9c2心肌细胞中肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-17、基质金属蛋白酶-2和基质金属蛋白酶-9的表达和浓度。使用Griess试剂测量一氧化氮（NO）的产生。使用ELISA检测肌酸激酶同工酶-MB（CK-MB）和心肌肌钙蛋白I（cTnI）的水平。利用蛋白质印迹法测定H9c2心肌细胞核中Toll样受体4（TLR4）、髓样分化因子88（MyD88）和p-NF-κB p65的表达。
首先，度拉糖肽通过抑制线粒体ROS的产生、提高还原型GSH水平以及下调NOX-1来改善LPS诱导的氧化应激。其次，度拉糖肽通过下调CK-MB和cTnI减轻LPS诱导的心肌细胞损伤，同时抑制iNOS表达和NO产生。最后，度拉糖肽通过抑制TLR4/Myd88/NF-κB信号通路，显著逆转了LPS诱导的炎症因子产生和MMPs上调。
度拉糖肽通过抑制炎症和氧化应激减轻LPS诱导的心肌细胞损伤。
