Zhang Dongyun, Wang Qun, Qiu Xunbin, Chen Yiguan, Yang Xiaoli, Guan Yujian
Department of Anesthesiology, Binhaiwan Central Hospital of Dongguan, Dongguan City, China.
School of Medicine, Jinan University, Guangzhou City, China.
J Pharm Pharmacol. 2022 Feb 1;74(2):282-291. doi: 10.1093/jpp/rgab151.
Myocardial I/R injury is one of the most serious complications after reperfusion therapy in patients with myocardial infarction. Remifentanil has been found to protect the heart against I/R injury. However, its underlying mechanism remains uncertain in myocardial I/R injury.
The myocardial I/R injury rat model was established by 30 min of ischaemia followed by 24 h of reperfusion. The animal model was evaluated by the levels of TC, ALT and AST and H&E staining. The binding of miR-206-3p and TLR4 was predicted and verified using TargetScan software, luciferase reporter and RNA pull-down assays. The functional role and mechanism of remifentanil were identified by ultrasonic echocardiography, oxidative stress markers, H&E, Masson and TUNEL staining and western blot.
The rat myocardial I/R injury model displayed a significantly high level of TC, ALT, AST, TLR4, p-IκBα and p-p65 and the presence of disorganized cells and inflammatory cell infiltration. The model also showed increased levels of LVEDD, LVESD, MDA, fibrosis and apoptosis and decreased levels of EF, FS, SOD and GSH, which were reversed with remifentanil treatment. Knockdown of miR-206-3p damaged cardiac function and aggravated oxidative stress. miR-206-3p could directly bind to TLR4. TLR4 overexpression destroyed cardiac function, exacerbated oxidative stress, increased levels of p-IκBα and p-p65 and aggravated pathology manifestation affected by remifentanil.
Our results elucidated that remifentanil alleviated myocardial I/R injury by miR-206-3p/TLR4/NF-κB signalling axis.
心肌缺血/再灌注损伤是心肌梗死患者再灌注治疗后最严重的并发症之一。已发现瑞芬太尼可保护心脏免受缺血/再灌注损伤。然而，其在心肌缺血/再灌注损伤中的潜在机制仍不确定。
通过30分钟缺血后再灌注24小时建立心肌缺血/再灌注损伤大鼠模型。通过总胆固醇（TC）、谷丙转氨酶（ALT）和谷草转氨酶（AST）水平以及苏木精-伊红（H&E）染色对动物模型进行评估。使用TargetScan软件、荧光素酶报告基因和RNA下拉实验预测并验证miR-206-3p与Toll样受体4（TLR4）的结合。通过超声心动图、氧化应激标志物、H&E、Masson和TUNEL染色以及蛋白质免疫印迹法确定瑞芬太尼的功能作用和机制。
大鼠心肌缺血/再灌注损伤模型显示TC、ALT、AST、TLR4、磷酸化IκBα（p-IκBα）和磷酸化p65（p-p65）水平显著升高，存在细胞排列紊乱和炎性细胞浸润。该模型还显示左室舒张末期内径（LVEDD）、左室收缩末期内径（LVESD）、丙二醛（MDA）、纤维化和凋亡水平升高，而射血分数（EF）、短轴缩短率（FS）、超氧化物歧化酶（SOD）和谷胱甘肽（GSH）水平降低，瑞芬太尼治疗可使其逆转。敲低miR-206-3p会损害心脏功能并加重氧化应激。miR-206-3p可直接与TLR4结合。TLR4过表达破坏心脏功能，加剧氧化应激，增加p-IκBα和p-p65水平，并加重受瑞芬太尼影响的病理表现。
我们的结果阐明了瑞芬太尼通过miR-206-3p/TLR4/核因子κB（NF-κB）信号轴减轻心肌缺血/再灌注损伤。
