橘皮素通过抑制ERK1/2信号通路干预小鼠腹主动脉瘤的进展

Tangeretin Attenuates Mouse Abdominal Aortic Aneurysm via Inhibiting ERK1/2 Signaling Pathway

目的探讨橘皮素对小鼠腹主动脉瘤模型的治疗机制。方法采用7~8周龄雄性ApoE^(-/-)小鼠行血管紧张素Ⅱ灌注并高脂饲养方法构建腹主动脉瘤模型,超声筛选造模成功的小鼠,随机分为对照组(生理盐水)和治疗组(橘皮素),每组各10只。治疗组每日给予1次灌胃橘皮素100 mg/kg,对照组给予等量生理盐水,4周后取材瘤体组织并石蜡包埋,行Masson和EVG法染色观察各组小鼠主动脉壁的病理和胶原沉积的变化,Western blot检测橘皮素对小鼠主动脉组织中ERK1/2信号通路的影响,免疫荧光染色检测主动脉壁MMP-2和MMP-9的表达。结果与对照组比较,治疗组血管紧张素Ⅱ诱导的主动脉直径的扩张和动脉壁弹力纤维的损坏均有一定程度的减轻(P<0.05);治疗组小鼠腹主动脉组织中ERK1/2及其磷酸化表达水平均下降(P<0.05),MMP-2和MMP-9的表达量同样减少(P<0.05)。结论Notch1信号抑制剂橘皮素同样能通过抑制ERK1/2信号通路和MMP-2、MMP-9的表达延缓小鼠动脉瘤的进展。

Objective To explore the therapeutic effect of Tangeretin on progression of abdominal aortic aneurysm(AAA)in mice.Methods 7~8 week of male ApoE^(-/-)mice were perfused with angiotensinⅡ(AngⅡ)and fed with high fat diet to establish AAA model.The AAA mice screened by ultrasound were randomly divided into control group(normal saline)and treatment group(Tangeretin)with each group of 10 mice.Mice in treatment group were gavaged with Tangeretin(100 mg/kg)once a day,and control group with same amount of saline.After 4 weeks,aneurysm tissues were harvested and embedded in paraffin.Masson and elastic-van Gieson staining(EVG)were performed to assess pathological changes of aorta wall and collagen deposition respectively in each group.Western blot was used to detect the effect of Tangeretin on ERK1/2 signaling pathway in mouse aortic tissue,and the expression of MMP-2 and MMP-9 in aortic wall were detected by immunofluorescence staining(IF).Results Compared with control group,the diameter dilation of AngⅡinduced AAA and destruction of elastic fibers in arterial wall were alleviated in treat group(P<0.05),levels of ERK1/2 protein and its phosphorylation in abdominal aortic wall tissue were decreased(P<0.05)and expressions of MMP-2 and MMP-9 were also decreased(P<0.05).Conclusion Notch1 signaling inhibitor Tangeretin can attenuate the progression of AAA by inhibiting ERK1/2 signaling pathway and expressions of MMP-2 and MMP-9 in ApoE-/-mice.