苦参碱调控mTOR/p70S6K信号通路对大鼠心肌肥厚的保护作用

目的:研究苦参碱对异丙肾上腺素致大鼠心肌肥厚的保护作用及其对mTOR/p70S6K信号通路的调控。方法:大鼠皮下注射异丙肾上腺素建立慢性病理性心肌肥厚模型,将大鼠随机分为正常对照组、异丙肾上腺素(ISO)模型组、苦参碱(50,100,200 mg·kg^-1·d^-1)+ISO组和单用苦参碱(200 mg·kg^-1·d^-1)组。HE染色观察心肌病理变化;Western blot检测左心室组织中mTOR/p70S6K信号通路相关蛋白的表达。结果:与正常对照组比较,ISO模型组大鼠的心肌细胞肥大、排列紊乱,可见不同程度的纤维化、间质水肿和炎细胞浸润;苦参碱(50,100,200 mg·kg^-1·d^-1)可减轻大鼠心肌细胞肥大、纤维化、间质水肿和炎细胞浸润等ISO致心肌组织病理学结构的异常改变。与正常对照组相比,ISO模型组心肌组织内p-mTOR、p-p70S6K和p70S6K的表达显著增加;苦参碱(50,100,200 mg·kg^-1)可逆转ISO致大鼠心肌组织中p70S6K表达的上调,同时下调mTOR Ser2448和p70S6K Thr389位点的磷酸化水平,且呈剂量依赖性;mTOR表达在各组之间均无差异;单用苦参碱组与正常对照组比较无显著性差异。结论:苦参碱具有抑制ISO致大鼠心肌肥厚的作用,其机制与抑制mTOR/p70S6K信号通路有关。

Protective effects of matrine on isoptroterenol-induced cardiac hypertrophy via regulation of mTOR/p70S6K signaling pathway in rats

OBJECTIVE To investigate the effects of matrine on regulation of mTOR/p70S6K signaling pathway and its protection of rats with ISO-induced cardiac hypertrophy, and elucidate its mechanism. METHODS Rat model of chronic pathologic cardiac hypertrophy was established by subcutaneous injection of ISO (5 mg·kg^-1·d^-1). Rats were randomly divided into normal control group, ISO model group, matrine (50, 100 and 200 mg·kg^-1·d^-1, respectively) + ISO groups and matrine-alone (200 mg·kg^-1·d^-1) group. After seven days of drug administration, cardiac apexes from rats in each-group were excised to observe myocardial pathology. Western blotting was utilized to detect mTOR/p-mTOR and p70S6K/p-p70S6K expressions in left ventricular tissues. RESULTS Compared with normal group, the cardiomyocytes of rats in ISO group showed myocardial fibrosis, interstitial edema and infiltration of inflammatory cells, whereas matrine could alleviate different degrees of histopathological abnormalities of cardiomyocyte induced by ISO. Compared with normal group, expressions of p-mTOR, p-p70S6K and p70S6K were markedly increased in myocardial tissues in rats in ISO group. Matrine down regulated the expression of p70S6K in myocardial tissues in rats. Simultaneously, it reduced the phosphorylation of mTOR Ser2448 and p70S6K Thr389 in a dose dependent manner. The levels of mTOR had no difference among all the groups. In contrast, those between matrine-alone group and normal group showed no significant difference. CONCLUSION Matrine can inhibit ISO-induced myocardial hypertrophy in rats and its mechanism may be related to regulation of mTOR/p70S6K signaling pathway.