基于ERK/p38 MAPK信号通路探讨芍药苷对顺铂诱导大鼠心功能障碍及心肌细胞损伤的影响

张诗捷; 田瑞琦; 丁银川; 武琦; 王沂然; 刘磊; 孙红; 薛敏

doi:10.13748/j.cnki.issn1007-7693.20233001

基于ERK/p38 MAPK信号通路探讨芍药苷对顺铂诱导大鼠心功能障碍及心肌细胞损伤的影响

Effects of Paeoniflorin on Cardiac Dysfunction and Myocardial Cell Injury Induced by Cisplatin in Rats Based on ERK/p38 MAPK Signaling Pathway

摘要

摘要:
目的探究芍药苷(paeoniflorin，PF)对顺铂(cisplatin，CDDP)诱导大鼠心功能障碍及心肌细胞损伤的保护作用。
方法 SD雄性大鼠随机分为对照组、CDDP组、CDDP+PF低剂量组及CDDP+PF高剂量组，PowerLab多功能记录仪进行左心室插管检测心功能相关指标左室内压峰值(left ventricular peak pressure，LVSP)、左室舒张末压(left ventricular end-diastolic pressure，LVEDP)、左室内压变化速率(±dp/dt)的数值变化；取各组大鼠血清，检测炎性因子TNF-α、IL-1β和IL-6水平；取心肌组织染色，观察组织结构变化。H9c2心肌细胞分为对照组、CDDP组、PF组及CDDP+PF组，CCK-8法测各组细胞活性；流式细胞术检测各组心肌细胞凋亡情况；Western blotting检测心肌细胞中MAPK信号通路相关蛋白p38、ERK、JNK及其磷酸化蛋白表达和凋亡相关蛋白Bax、Bcl-2、Casp3、Cl-casp3的表达情况。
结果与对照组相比，CDDP组LVSP、±dp/dt明显下降(P<0.01)，LVEDP明显升高 (P<0.01)；与CDDP组比较，PF低、高剂量预处理均可升高LVSP及±dp/dt水平 (P <0.05或P<0.01)，降低LVEDP水平 (P<0.01)，降低大鼠血清中炎性因子TNF-α、IL-1β和IL-6 含量 (P<0.01)。细胞水平结果显示，与对照组相比，CDDP组细胞活性下降，凋亡相关蛋白Bax 、Cl-casp3表达增加(P<0.01)，抗凋亡蛋白Bcl-2表达降低(P<0.01)，MAPK通路p38及ERK磷酸化表达升高(P<0.01)；与CDDP组相比，PF可恢复细胞活性，下调凋亡相关蛋白Bax、Cl-casp3表达(P<0.05或P<0.01)，增加抗凋亡蛋白Bcl-2表达(P<0.01)，抑制MAPK通路p38及ERK磷酸化表达(P<0.01)。
结论 PF可恢复CDDP诱导大鼠心功能障碍及心肌细胞损伤，其作用可能通过调控ERK/p38 MAPK信号抑制炎症反应和细胞凋亡。

Abstract:
OBJECTIVE To investigate the protective effect of paeoniflorin(PF) on cardiac dysfunction and myocardial cell injury induced by cisplatin(CDDP) in rats.
METHODS SD male rats were randomly divided into control group, CPPD group, and CDDP PF+low-dose, high-dose group. PowerLab multifunctional recorder was used to detect the related indexes of cardiac function: the changes of left ventricular peak pressure(LVSP), left ventricular end-diastolic pressure(LVEDP) and left ventricular pressure change rate(±dp/dt). Serum levels of inflammatory factors TNF-α, IL-1β and IL-6 were measured in each group. Myocardial tissue was stained to observe the changes of tissue structure. H9c2 cardiomyocytes were divided into control group, CDDP group, PF group and CDDP+PF group. The activity of H9c2 cardiomyocytes was measured by CCK-8. The apoptosis of cardiomyocytes in each group was detected by flow cytometry. The expressions of MAPK signaling pathway related proteins p38, ERK, JNK and their phosphorylated proteins and apoptosis-related proteins Bax, Bcl-2, Casp3, Cl-casp3 were detected in cardiomyocytes by Western blotting.
RESULTS Compared with the control group, LVSP and ±dp/dt decreased, LVEDP increased in rats of CDDP group(P<0.01). Compared with CDDP group, both CDDP+low-dose and high-dose PF pretreatment increased LVSP and ±dp/dt value(P<0.05 or P<0.01), decreased LVEDP(P<0.01), and could decrease the serum inflammatory factor TNF-α, IL-1β and IL-6(P<0.01). Cell level results showed that compared with control group, in CDDP group, the cell activity decreased, the apoptosis-related protein Bax, Cl-casp3 increased(P<0.01), expression of anti-apoptotic protein Bcl-2 decreased(P<0.01), and the expression of p38 and ERK phosphorylation also increased(P<0.01). Compared with CDDP group, PF could restore cell activit, down-regulate apoptosis-related protein Bax, Cl-casp3(P<0.05 or P<0.01), and increase anti-apoptotic protein Bcl-2 expression(P<0.01), inhibit MAPK pathway p38 and ERK phosphorylation expression(P<0.01).
CONCLUSION PF can restore cardiac dysfunction and myocardial cell injury induced by cisplatin in rats, which may be related to inhibiting inflammation and apoptosis by regulating ERK/p38 MAPK signal expression.

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