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    SOCS2调节PI3K/AKT轴对多柔比星诱导的大鼠心力衰竭和心肌细胞凋亡的影响

    Effects of SOCS2 on Doxorubicin-induced Heart Failure and Cardiomyocyte Apoptosis in Rats by Regulating PI3K/AKT Axis

      摘要
    • 摘要:
      目的  探讨细胞因子信号抑制因子2(suppressor of cytokine signaling 2，SOCS2)调节磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase，PI3K)/蛋白激酶B(protein kinase B，AKT)信号通路对多柔比星诱导的大鼠心力衰竭及心肌细胞凋亡的影响。
      方法 50只雄性Sprague-Dawley大鼠随机分为5组(n=10)：对照组、多柔比星模型组、SOCS2低剂量组(0.5 mg·kg−1)、SOCS2中剂量组(1.0 mg·kg−1)及SOCS2高剂量组(2.0 mg·kg−1)。多柔比星模型组及SOCS2低、中、高剂量组通过尾静脉注射多柔比星(2.5 mg·kg−1，每周1次，连续6周，总剂量15 mg·kg−1)建立心力衰竭模型，对照组注射等体积生理盐水。SOCS2低、中、高剂量组在造模同期每周注射相应剂量SOCS2重组蛋白，干预周期共6周，总实验周期为8周(包括第1~2周的基础心功能测定与分组适应期)。实验第8周末，采用超声心动图测定左心室内径舒张末期(left ventricular end-diastolic diameter，LVEDD)、左心室内径收缩末期(left ventricular end-systolic diameter，LVESD)、短轴缩短率(fractional shortening，FS)及射血分数(ejection fraction，EF)；Masson染色评估胶原容积分数(collagen volume fraction，CVF)及血管周围胶原面积(perivascular collagen area，PVCA)；TUNEL染色检测心肌细胞凋亡率；RT-qPCR及Western blotting检测PI3K、AKT mRNA及蛋白表达水平。
      结果 与对照组比较，多柔比星模型组LVEDD、LVESD、CVF、PVCA、心肌细胞凋亡率显著升高，FS、EF水平显著降低(P<0.05)；与多柔比星模型组比较，SOCS2低、中、高剂量组中，上述心功能及纤维化指标均得到改善，心肌细胞凋亡率降低，且PI3K、AKT mRNA及蛋白表达升高，各指标均呈现明显的剂量-效应关系(P<0.05)。
      结论 SOCS2重组蛋白可能通过上调PI3K/AKT通路活性，剂量依赖性地改善多柔比星诱导的大鼠心力衰竭，减轻心肌纤维化及细胞凋亡，提示SOCS2为潜在的药物性心肌病治疗靶点。

       

      Abstract:
      OBJECTIVE To investigate the effect of suppressor of cytokine signaling 2(SOCS2) on doxorubicin-induced heart failure and cardiomyocyte apoptosis in rats by regulating phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) signaling pathway.
      METHODS Fifty male Sprague-Dawley rats were randomly divided into 5 groups(n=10): control group, doxorubicin model group, SOCS2 low dose group(0.5 mg·kg−1), SOCS2 medium dose group(1.0 mg·kg−1), and SOCS2 high dose group(2.0 mg·kg−1). The doxorubicin model group and SOCS2 low, medium and high dose groups were injected with doxorubicin(2.5 mg·kg−1, once a week for 6 weeks, total dose 15 mg·kg−1) via the tail vein to establish heart failure models, while the control group was injected with an equal volume of normal saline. The SOCS2 low, medium and high dose groups were injected with the corresponding dose of SOCS2 recombinant protein weekly during the 6-week modeling period. The total experimental period was 8 weeks(including a 1−2 week baseline cardiac function measurement and acclimation period). At the end of the 8th week, left ventricular end-diastolic diameter(LVEDD), left ventricular end-systolic diameter(LVESD), fractional shortening(FS), and ejection fraction(EF) were measured by echocardiography. Collagen volume fraction(CVF) and perivascular collagen area(PVCA) were assessed by Masson’s staining. Cardiomyocyte apoptosis rate was detected by TUNEL staining. The expression levels of PI3K and AKT mRNA and protein were detected by RT-qPCR and Western blotting, respectively.
      RESULTS Compared with the control group, the LVEDD, LVESD, CVF, PVCA, and cardiomyocyte apoptosis rate of doxorubicin model group were increased, while the level of FS and EF were decreased(P<0.05). Compared with the doxorubicin model group, the SOCS2 low, medium and high groups showed improved cardiac function and fibrosis indices, decreased cardiomyocyte apoptosis rate, and increased expression of PI3K and AKT mRNA and protein, all indicators exhibited a clear dose-response relationship(P<0.05).
      CONCLUSION SOCS2 recombinant protein may dose-dependently improve doxorubicin-induced heart failure in rats, reduce myocardial fibrosis and apoptosis by up-regulating the activity of the PI3K/AKT pathway, suggesting that SOCS2 is a potential therapeutic target for drug-induced cardiomyopathy.

       

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