目的 探讨Notch1/Hes1信号在白藜芦醇减轻大鼠川崎病(KD)诱发心肌损伤中的作用。方法 将48只幼年雄性SD大鼠(4周龄)随机分为对照组(Control)、白藜芦醇对照组(Res)、干酪乳杆菌细胞壁提取物(LCWE)注射模拟川崎病组(KD)和KD联合白藜芦醇组(Res+KD),对照组腹腔注射生理盐水,Res组腹腔注射Res(100 mg/kg),KD组腹腔注射LCWE(1 mg/ml),而KD+Res组腹腔注射LCWE(1 mg/ml)和Res(100 mg/kg)。4周后,小动物超声检测各组心脏功能并计算左室射血分数(LVEF)和短轴缩短率(LVFS),HE染色观察心肌形态,酶联免疫吸附法(ELISA)检测心肌组织中TNF-α和IL-1β含量,TUNEL染色观察细胞凋亡的变化,Western blot检测心肌组织中凋亡相关蛋白Bcl2和Bax的蛋白含量以及Notch1和Hes1信号的变化。结果 Res组各项检测指标与对照组相比均无统计学差异;与对照组相比,KD组发生心脏功能障碍和心肌细胞凋亡增加,表现为LVEF和LVFS明显降低(P<0.05),Bax蛋白表达与凋亡指数增加,Bcl2蛋白表达降低(P<0.05),心肌组织中TNF-α和IL-1β含量增加(P<0.05),HE染色显示心肌纤维排列紊乱并有断裂现象,同时,心肌组织中Notch1和Hes1蛋白表达显著降低(P<0.05);而与KD组比较,Res处理后,可改善KD引起的心脏功能障碍和细胞凋亡,降低心肌组织中TNF-α和IL-1β含量(P<0.05),改善心肌纤维排列,并增加心肌组织Notch1和Hes1蛋白表达(P<0.05)。结论 KD会导致心脏功能障碍和心肌细胞凋亡增加,同时引起心肌组织炎性反应,抑制Notch1/Hes1信号;而Res可通过激活Notch1/Hes1信号减轻心肌组织和冠状动脉炎症,改善KD引起的心肌损伤。
Abstract
Objective To investigate the role of resveratrol (Res) in Kawasaki disease-induced myocardial injury and the effect of Notch1/Hes1 signaling pathway.Methods Forty-eight young male SD rats were randomly divided into the control group,Res group,LCWE-induced Kawasaki disease group (KD),and Res treatment group (Res+KD).The control group was intraperitoneally injected with 0.5 ml saline,Res group with resveratrol (100 mg/kg),KD group with 0.5 ml LCWE (1 mg/ml),and Res+KD group with 0.5 ml LCWE (1 mg/ml) and resveratrol (100 mg/kg).After four weeks,the rat cardiac function was tested by ultrasonic testing,and myocardial TNF-α and IL-1β contents were detected by ELISA.The apoptotic index was detected by TUNEL staining.The morphological changes in myocardial fibers were analyzed via HE staining.Western blot was used to detect the protein levels of Bcl2,Bax,Notch1,and Hes1.Results There was no significant difference between the Res group and the control group (P>0.05).Compared with the control group,the left ventricular ejection fraction (LVEF),fractional shortening (LVFS) and expression of Bcl2 were significantly decreased in the KD group (P<0.05),but the expression of Bax was increased (P<0.05).The myocardial TNF-α and IL-1β contents and apoptotic index were increased (P<0.05),while the levels of Notch1 and Hes-1 were reduced (P<0.05).Res could alleviate myocardial injury induced by KD and reduce the inflammation in the myocardium (P<0.05).Conclusions KD can induce myocardial injury by increasing apoptosis and inflammation via inhibition of Notch1/Hes1 signaling.Res can activate Notch1/Hes1 signaling to inhibit myocardial apoptosis and inflammation and improve cardiac function in case of KD-induced myocardial injury.
关键词
川崎病 /
心肌凋亡 /
炎性反应 /
Notch1/Hes1
Key words
Kawasaki disease /
apoptosis /
inflammation /
Notch1/Hes1
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基金
陕西省自然科学基础研究计划一般项目(2019JQ-544)
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