Combination of Ligusticum Chuanxiong and Radix Paeonia Promotes Angiogenesis in Ischemic Myocardium through Notch Signalling and Mobilization of Stem Cells
Combination of Ligusticum Chuanxiong and Radix Paeonia Promotes Angiogenesis in Ischemic Myocardium through Notch Signalling and Mobilization of Stem Cells
复制标题
川芎和芍药组合通过Notch信号传导和干细胞动员促进缺血心肌血管生成
DOI：
10.1155/2019/7912402
复制
发表时间：
2019-01-01
影响因子：
--
通讯作者：
Chen, Ke-Ji
中科院分区：
文献类型：
--
作者：
Shi, Wei-Li;Zhao, Jun;Chen, Ke-Ji
目的探讨赤芍与丹参合用促进血管生成的心肌保护机制。方法采用结扎冠状动脉左前降支的方法建立小鼠心肌梗死模型。观察培哚普利叔丁胺组（PB组）（3 mg/kg/d）、CX组（55 mg/kg/d）、CS组（55 mg/kg/d）、CX + CS联合组（CX + CS）（27.5 mg/kg/d）对心功能的影响。使用Notch γ分泌酶抑制剂RO 4929097（10 mg/kg/d）探索Notch信号传导在CX-CS诱导的心肌梗死边缘区（IBZ）血管生成促进中的作用。采用动物超声和Masson染色法测定左室射血分数（LVEF）和心肌梗死面积百分比。免疫荧光法检测心肌IBZ内CD 31和vWF的平均光密度值（AODs）。Western blot检测血管生成相关蛋白包括缺氧诱导因子1 α（HIF-1α）、成纤维细胞生长因子受体1（FGFR-1）、Notch 1和Notch胞内结构域（NICD），以及干细胞动员相关蛋白包括基质细胞衍生因子1（SDF-1）、C-X-C趋化因子受体4（CXCR-4）和心肌营养素1（cardiotrophin 1）。结果与模型组比较，治疗21 d后，CX-CS组和PB组LVEF明显改善，心肌梗死面积百分比明显降低。CX组和CS组与模型组比较，LVEF增加，MI面积减小，但差异无统计学意义。模型组和CX-CS-I组大鼠IBZ区CD 31的AOD值均较假手术组明显降低。与模型组相比，CX-CS可显著增加IBZ区CD 31的AOD，降低梗死区CD 31和vWF的AOD。模型组和CX-CS组HIF-1α的表达均高于Sham组。与模型组比较，CX-CS组FGFR-1、SDF-1、cardiotrophin 1、Notch 1、NICD表达均增加。与CX-CS组相比，CX-CS-I组的Notch 1和NICD表达减少。结论CX和CS联合应用对IBZ心肌细胞的保护作用优于单独应用CX或CS。CX-CS保护缺血心肌的机制可能与CX-CS通过Notch信号传导和动员干细胞到IBZ发挥促血管生成作用有关。
Objective To study the cardioprotective mechanism by which the combination of Chuanxiong (CX) and Chishao (CS) promotes angiogenesis. Methods Myocardial infarction (MI) mouse models were induced by ligation of the left anterior descending coronary artery. The effects on cardiac function were evaluated in the perindopril tert-butylamine group (PB group) (3 mg/kg/d), CX group (55 mg/kg/d), CS group (55 mg/kg/d), and CX and CS combination (CX-CS) group (27.5 mg/kg/d CX plus 27.5 mg/kg/d CS). RO4929097, an inhibitor of Notch γ secretase, was used (10 mg/kg/d) to explore the role of Notch signalling in the CX-CS-induced promotion of angiogenesis in the myocardial infarcted border zone (IBZ). The left ventricular ejection fraction (LVEF) and percentage of MI area were evaluated with animal ultrasound and Masson staining. The average optical densities (AODs) of CD31 and vWF in the myocardial IBZ were detected by immunofluorescence. Angiogenesis-related proteins including hypoxia-inducible factor 1-alpha (HIF-1α), fibroblast growth factor receptor 1 (FGFR-1), Notch1 and Notch intracellular domain (NICD), and stem cell mobilization-related proteins including stromal cell-derived factor 1 (SDF-1), C-X-C chemokine receptor type 4 (CXCR-4), and cardiotrophin1 were detected by western blot analysis. Results Compared with the model group, the CX-CS and PB groups both showed markedly improved LVEF and decreased percentage of MI area after 21 days of treatment. Although the CX group and CS group showed increased LVEF and decreased MI areas compared with the model group, the difference was not significant. The AOD of CD31 in the IBZ in both the model and the CX-CS-I group was markedly reduced compared with that in the sham group. CX-CS significantly increased the CD31 AOD in the IBZ and decreased the AODs of CD31 and vWF in the infarct zone compared with those in the model group. The expression of HIF-1α in both the model group and the CX-CS group was higher than that in the sham group. Compared with the model group, the expression of FGFR-1, SDF-1, cardiotrophin1, Notch1, and NICD was increased in the CX-CS group. Notch1 and NICD expression in the CX-CS-I group was reduced compared with that in the CX-CS group. Conclusions The combination of CX and CS protected cardiomyocytes in the IBZ better than CX or CS alone. The mechanism by which CX-CS protects ischemic myocardium may be related to the proangiogenesis effect of CX-CS exerted through Notch signalling and the mobilization of stem cells to the IBZ.