川芎嗪通过激活Akt/eNOS通路预防阿霉素致小鼠心脏毒性

Ligustrazine prevents doxorubicin-induced cardiotoxicity in mice via activating Akt/eNOS signaling pathway

目的研究川芎嗪对阿霉素诱导的小鼠心脏毒性的预防作用及其机制。方法建立阿霉素诱导的心脏毒性小鼠模型,将小鼠随机分为3组：对照组、阿霉素组（阿霉素15 mg/kg）、川芎嗪组[川芎嗪60 mg/（kg·d）＋阿霉素15 mg/kg],心脏超声检测川芎嗪干预后阿霉素对小鼠心脏功能的影响,HE染色及Masson三色染色检测小鼠心脏组织学及胶原蛋白的变化,TUNEL染色检测小鼠心肌细胞凋亡情况,Western blot检测p-Akt、Akt、p-eNOS、eNOS及cleaved Caspase-3蛋白的表达。结果与阿霉素组相比,川芎嗪组左心室短轴缩短率（FS）和左心室射血分数（EF）显著升高（P〈0.01）;川芎嗪显著降低小鼠心肌细胞凋亡（P〈0.01）,明显抑制小鼠心肌纤维化和炎症细胞浸润（P〈0.01）;与阿霉素组相比,川芎嗪组显著上调p-Akt和p-eNOS的表达（P〈0.05）,显著下调cleaved Caspase-3的表达（P〈0.01）。结论川芎嗪通过激活Akt/eNOS通路抑制心肌细胞凋亡保护阿霉素诱导损伤心肌可能是川芎嗪预防阿霉素致心脏毒性的一个潜在机制。

Aim To study the preventive effect and mechanism of ligustrazine on doxorubicin-induced cardiotoxicity in mice. Methods The mouse model of cardiotoxicity induced by doxorubicin was established. The mice were randomly divided into three groups： sham group,doxorubicin group（ doxorubicin 15 mg/kg）,ligustrazine treated group（ ligustrazine 60 mg/（ kg·d） ＋doxorubicin 15 mg/kg）,echocardiography was performed to detect cardiac function of doxorubicin and ligustrazine intervention groups in mice. The sections were stained with HE staining or Masson’s trichrome staining for histological and collagen analysis,apoptosis of cardiomyocyte were analyzed by TUNEL staining,Western blot was used to analyze the expression of Akt,endothelial nitric oxide synthase（ eNOS）,the phosphorylation of Akt and eNOS.Results Compared with doxorubicin group,the fractional shortening（ FS） and the ventricular ejection fraction（ EF） in the ligustrazine treated group were significantly higher（ P 〈 0. 01）. The ligustrazine treated group significantly decreased apoptosis of cardiomyocyte in mice as compared to the doxorubicin group（ P〈0.01）,the expression of p-Akt and p-eNOS in the ligustrazine treated group were stronger than those in the the doxorubicin group（ P〈 0.01）. Meanwhile,the ligustrazine treated group significantly inhibited cleaved Caspase-3 as compared to the doxorubicin group. Conclusion Ligustrazine protects doxorubicin-induced myocardial injury by activating Akt/eNOS signaling pathway and inhibiting cardiomyocyte apoptosis,and it may be an underlying mechanism by which ligustrazine can prevent doxorubicin-induced cardiotoxicity.