Epac1-Rap1通路介导牡荆素对大鼠慢性心肌缺血再灌注损伤的保护作用

Effect of vitexin on myocardial ischemia/reperfusion injury in rats via Epac1-Rap1 signaling pathway

目的:研究Epac1-Rap1通路介导牡荆素对大鼠慢性心肌缺血再灌注损的保护作用。方法:将48只清洁级雄性SD大鼠随机分为6组:假手术组、模型组、牡荆素组(6、3、1.5mg/kg)和灯盏花素(3mg/kg)阳性对照药组。采用结扎大鼠左冠状动脉前降支(缺血1 h再灌注14天)建立慢性心肌缺血再灌注损伤(myocardial ischemial reperfusion injury,MIRI)模型。记录大鼠不同时间点心电图ST段的变化,颈动脉插管检测大鼠左心功能变化,病理观察心肌纤维化程度,检测大鼠血清中还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、超氧化物歧化酶(SOD)、丙二醛(MDA)的水平以及心肌组织中Epac-1、Rap-1、Bax和Bcl-2蛋白表达,以此探索牡荆素在减轻大鼠慢性心肌缺血再灌注损伤中的作用机制。结果:与模型组相比,牡荆素用药组大鼠ST段的抬高幅度明显减小,血清中MDA含量降低,SOD和NADPH含量增高;牡荆素6、3mg/kg剂量组能明显改善慢性心肌缺血大鼠左心室功能并抑制心肌反应性纤维化的程度,同时能增加Bcl-2的蛋白表达,抑制Epac-1、Rap1、Bax蛋白过度表达。结论:牡荆素可以减轻大鼠慢性心肌缺血再灌注损伤,其机制与抑制脂质过氧化、调控心肌细胞Epac-1/Rap-1信号途径并抑制心肌细胞凋亡作用有关。

Objective ： To study the cardioprotective effect of vitexin on chronic myocardial ischemia/reperfusion injury in rats via Epacl -Rapl signaling pathway. Methods：48 male Sprague-Dawley （SD） rats were divided randomly into 6 groups： the sham group, the model group, the three vitexin treated groups （6, 3, 1.5mg/kg） and a positive control group （treated with 3mg/kg breviscapine）. Rats＇chronic myocardial ischemia reperfusion injury （MIRI） models were established by ligating left anterior descending coronary artery for 1 hour and followed by reperfusion for 14 days. Changes of the ST segment of the electrocardiogram were recorded, functional changes of the left ventricular were observed by carotid artery intubation. Degree of myocardial fibrosis were observed, serum levels of reduced nicotinamide adenine dinucleotide phosphate （NADPH）, superoxide dismutase （SOD） and methane dicarboxylic aldehyde （MDA） and the expression of Epac-1, Rap-1, Bax and Bcl-2 proteins in cardiac muscle tissue were detected to explore the protective mechanism of vitexin on myocardial ischemia reperfusion injury in rats. Results： Compared with the model group, the elevated scope of ST segment of the rats in vitexin groups were considerably re- duced, and the serum level of MDA was lowered. SOD and NADPH levels were increased. In addition, Vitexin at 6 and 3 mg/kg doses significantly improved the left ventricular function on chronic myocardial ischemia/reperfusion in rats, inhibited myocardial reactive fibrosis, increased the expression of Bcl-2 protein and suppressed the over expression of Epac-1, Rap-1 and Bax. Conclusions： Vitexin could alleviate the myocardial ischemia reperfusion injury in rats, and its mechanism is related to the suppression of lipid peroxidation, regulation of Epac-1/ Rap-1 signal pathway in myocardial cells and the suppression of myocardium cell apoptosis.