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红景天苷调节PINK1/Parkin信号通路对缺血性心肌病大鼠线粒体自噬的影响

Impacts of salidroside on mitochondrial autophagy in ischemiccardiomyopathy rats by regulating the PINK1/Parkin signaling pathway

    摘要
  • 摘要:
    目的  探讨红景天苷(Sal)调节PTEN诱导激酶1(PINK1)/E3泛素连接酶(Parkin)信号通路对缺血性心肌病(ICM)大鼠线粒体自噬的影响。
    方法  将30只SD大鼠随机分为对照组、模型组、Sal低剂量组、Sal高剂量组、线粒体自噬抑制剂(Mdivi-1)组和Sal高剂量+Mdivi-1组，每组5只。构建ICM大鼠模型。分析各组大鼠左室射血分数(LVEF)、左室缩短分数(LVFS)、左室舒张末期内径(LVIDd)和左室收缩末期内径(LVIDs)。采用酶联免疫吸附测定(ELISA)检测各组大鼠血清乳酸脱氢酶(LDH)、肌钙蛋白I(cTnI)、肌酸激酶同工酶(CK)、N末端B型利钠肽原(NT-proBNP)水平。采用苏木素-伊红(HE)染色观察各组大鼠心肌组织病理变化，采用透射电子显微镜观察心肌组织线粒体结构。测定各组大鼠活性氧(ROS)、丙二醛(MDA)、超氧化物歧化酶(SOD)水平。采用蛋白质免疫印迹(Western blot)检测心肌组织微管相关蛋白轻链3(LC3)、肌球蛋白样Bcl-2结合蛋白(Beclin1)、泛素结合蛋白(p62)、PINK1、Parkin蛋白的表达水平。
    结果  与对照组比较，模型组心肌组织病理损伤加重，线粒体损伤明显。模型组LVEF、LVFS、SOD、p62水平低于对照组, LVIDd、LVIDs、LDH、cTnI、CK、NT-proBNP、ROS、MDA、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平高于对照组，差异有统计学意义(P < 0.05)。与模型组比较, Sal低剂量组、Sal高剂量组心肌组织损伤和线粒体损伤减轻。Sal低剂量组、Sal高剂量组LVEF、LVFS、SOD、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平高于模型组, LVIDd、LVIDs、LDH、cTnI、CK、NT-proBNP、ROS、MDA、p62水平低于模型组，差异有统计学意义(P < 0.05)。与模型组比较, Mdivi-1组心肌组织病理损伤加重，线粒体损伤明显。Mdivi-1组LVEF、LVFS、SOD、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平低于模型组, LVIDd、LVIDs、LDH、cTnI、CK、NT-proBNP、ROS、MDA、p62水平高于模型组，差异有统计学意义(P < 0.05)。与Sal低剂量组比较, Sal高剂量组心肌组织损伤改善，线粒体损伤减轻。Sal高剂量组LVEF、LVFS、SOD、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平高于Sal低剂量组, LVIDd、LVIDs、LDH、cTnI、CK、NT-proBNP、ROS、MDA、p62水平低于Sal低剂量组，差异有统计学意义(P < 0.05)。Mdivi-1可显著抑制线粒体自噬，并抑制Sal对心肌组织PINK1/Parkin信号通路的激活和心功能的改善(P < 0.05)。
    结论  Sal可能通过激活PINK1/Parkin信号通路，促进ICM大鼠线粒体自噬，进而改善大鼠心肌损伤。

     

    Abstract:
    Objective  To investigate the effects of salidroside (Sal) on mitochondrial autophagy in ischemic cardiomyopathy (ICM) rats by modulating the PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) signaling pathway.
    Methods  Thirty SD rats were randomly divided into control group, model group, low-dose Sal group, high-dose Sal group, mitochondrial autophagy inhibitor (Mdivi-1) group and high-dose Sal + Mdivi-1 group, with five rats in each group. The ICM rat model was established. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVIDd) and left ventricular end-systolic diameters (LVIDs) were analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase (CK) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Hematoxylin and eosin (HE) staining was performed to observe pathological changes in myocardial tissue, and transmission electron microscopy was used to examine mitochondrial structure. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Western blot analysis was conducted to determine the expression levels of microtubule-associated protein light chain 3 (LC3), Beclin1, p62, PINK1 and Parkin in myocardial tissue.
    Results  Compared with the control group, the model group showed more severe myocardial tissue and mitochondrial damage. The LVEF, LVFS, SOD and p62 levels in the model group were significantly lower than those in the control group, while the LVIDd, LVIDs, LDH, cTnI, CK, NT-proBNP, ROS, MDA, LC3II/LC3I, Beclin1, PINK1 and Parkin levels were significantly higher (P < 0.05). Compared with the model group, the low-dose and high-dose Sal groups exhibited reduced myocardial and mitochondrial damage. The LVEF, LVFS, SOD, LC3II/LC3I, Beclin1, PINK1 and Parkin levels in the low-dose and high-dose Sal groups were significantly higher than those in the model group, while the LVIDd, LVIDs, LDH, cTnI, CK, NT-proBNP, ROS, MDA and p62 levels were significantly lower (P < 0.05). Compared with the model group, the Mdivi-1 group showed more severe myocardial and mitochondrial damage. The LVEF, LVFS, SOD, LC3II/LC3I, Beclin1, PINK1 and Parkin levels in the Mdivi-1 group were significantly lower than those in the model group, while the LVIDd, LVIDs, LDH, cTnI, CK, NT-proBNP, ROS, MDA and p62 levels were significantly higher (P < 0.05). Compared with the low-dose Sal group, the high-dose Sal group demonstrated further improvement in myocardial and mitochondrial damage. The LVEF, LVFS, SOD, LC3II/LC3I, Beclin1, PINK1 and Parkin levels in the high-dose Sal group were significantly higher than those in the low-dose Sal group, while the LVIDd, LVIDs, LDH, cTnI, CK, NT-proBNP, ROS, MDA and p62 levels were significantly lower (P < 0.05). Mdivi-1 significantly inhibited mitochondrial autophagy and suppressed the activation of the PINK1/Parkin signaling pathway and the improvement in cardiac function induced by Sal (P < 0.05).
    Conclusion  Sal may improve myocardial injury in ICM rats by activating the PINK1/Parkin signaling pathway and promoting mitochondrial autophagy.

     

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