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    藏药二十味沉香丸对低氧性肺动脉高压大鼠心肌纤维化的保护作用及机制研究

    Study on the Protective Effect and Mechanism of Tibetan Medicine Ershiwei Chenxiang Wan on Myocardial Fibrosis in Rats with Hypoxic Pulmonary Hypertension

      摘要
    • 摘要:
      目的  探讨藏药二十味沉香丸(Ershiwei Chenxiang Wan，ECW)对低氧性肺动脉高压(hypoxic pulmonary hypertension，HPH)大鼠心肌纤维化的保护作用及潜在机制。
      方法 雄性SD大鼠60只，随机分为空白对照组、HPH组、HPH+0.6 g·kg−1 ECW组、HPH+1.2 g·kg−1 ECW组、HPH+曲美他嗪(trimetazidine，TMZ)组，除空白对照组组外，其余各组皮下注射塞马西尼(SU5416)后，置于低压氧舱3周，每天开舱1 h灌胃给药，记录大鼠体质量。实验结束后，检测大鼠肺动脉压、右心室压，血细胞计数，血清生化检测NT-proBNP、CK-MB、LDH含量，计算大鼠右心肥厚指数和心脏系数，HE、Masson染色观察心脏组织病理改变及纤维化程度，Western blotting检测大鼠心肌CollagenⅠ、OPN、Akt、pAkt、GSK-3β、pGSK-3β和β-catenin蛋白表达。
      结果 与空白对照组比较，HPH组大鼠体质量增长缓慢，红细胞增多；肺动脉压、右心室压升高；血清中NT-proBNP、CK-MB、LDH水平升高；心脏质量系数、富尔顿指数增大；心肌出现纤维化，CollagenⅠ表达增多；OPN、pAkt、pGSK-3β和β-catenin表达增加。经ECW干预后，上述异常指标均得到不同程度改善，其中1.2 g·kg−1 ECW干预效果更显著。
      结论 藏药二十味沉香丸可有效缓解HPH大鼠心肌损伤，其机制可能与抑制OPN/Akt/GSK-3β信号通路的激活，下调通路相关蛋白表达，进而减轻心肌纤维化进程有关。

       

      Abstract:
      OBJECTIVE To investigate the protective effect and potential mechanism of Tibetan medicine Ershiwei Chenxiang Wan(ECW) on myocardial fibrosis in rats with hypoxic pulmonary hypertension(HPH).
      METHODS Sixty male SD rats were randomly divided into 5 groups: the control group, HPH group, HPH+0.6 g·kg−1 ECW group, HPH+1.2 g·kg−1 ECW group, and HPH+TMZ group. Except for the control group, rats in the other groups were subcutaneously injected with semaxinib(SU5416), and then placed in a hypobaric oxygen chamber for 3 weeks, with the chamber opened for 1 h daily for intragastric administration. The body weight of rats was recorded every day. At the end of the experiment, pulmonary artery pressure(PAP) and right ventricular pressure(RVP) were measured; blood cell count was performed; serum levels of N-terminal pro-brain natriuretic peptide(NT-proBNP), creatine kinase isoenzyme MB(CK-MB) and lactate dehydrogenase(LDH) were detected by serum biochemical assays; the right ventricular hypertrophy index and cardiac index of rats were calculated; HE staining and Masson staining were used to observe the pathological changes and fibrosis degree of cardiac tissues; Western blotting was applied to determine the protein expressions of Collagen Ⅰ, osteopontin(OPN), Akt, phosphorylated Akt(pAkt), glycogen synthase kinase-3β(GSK-3β), phosphorylated GSK-3β(pGSK-3β) and β-catenin in myocardial tissues.
      RESULTS Compared with the control group, rats in the HPH group showed slow body weight gain, increased red blood cell count, elevated PAP and RVP, higher serum levels of NT-proBNP, CK-MB and LDH, increased cardiac index and Fulton index, obvious myocardial fibrosis, up-regulated expression of Collagen Ⅰ, as well as increased expressions of OPN, pAkt, pGSK-3β and β-catenin. After intervention with ECW, all the above abnormal indicators were improved to varying degrees, with more remarkable effects observed in the 1.2 g·kg−1 ECW group.
      CONCLUSION Tibetan medicine ECW can effectively alleviate myocardial injury in HPH rats, and its mechanism may be related to inhibiting the activation of OPN/Akt/GSK-3β signaling pathway, down-regulating the expression of pathway-related proteins, thereby reducing the process of myocardial fibrosis.

       

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