The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway.
The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway.
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DOI：
10.1371/journal.pone.0102292
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Xu T;Wu X;Chen Q;Zhu S;Liu Y;Pan D;Chen X;Li D
本研究旨在观察丹酚酸A(SAA)对缺血/再灌注(I/R)心肌的影响，阐明心肌I/R过程中双特异性蛋白磷酸酶(DUSP)2/4/16、ERK1/2和JNK信号通路之间的相互关系，以阐明SAA对心肌I/R损伤(IRI)的保护作用。Wistar大鼠分为6组：对照组(CON)、I/R组、SAA+I/R组、ERK1/2抑制剂PD098059+I/R组(PD+I/R)、PD+SAA+I/R组、JNK抑制剂SP600125+I/R组(SP+I/R)。用朗宁多夫装置观察SAA对I/R心肌的保护作用。监测心率(HR)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室内压最大上升和下降速率(±dp/dtmax)、心肌梗死面积(MIA)、乳酸脱氢酶(LDH)和心肌细胞凋亡率。用siRNA-DUSP2/4/16检测经SAA处理后的JNK和ERK1/2之间的串扰。Western印迹法检测心肌细胞中Bcl2、Bax、caspase3、p-JNK、p-ERK1/2和DUSP2/4/16的表达水平。结果表明，SAA预处理和SP应用可降低心肌LDH、MIA和细胞凋亡率，改善心功能各项指标。在I/R组，p-ERK1/2和DUSP4/16的表达水平与CON组无显著差异，而SAA+I/R组、PD+SAA+I/R组和SP+I/R组的p-ERK1/2、Bcl2和DUSP4/16的蛋白表达水平高于CON组，而p-JNK、Bax、caspase 3和DUSP2的蛋白表达水平低于CON组。SAA+I/R组与SP+I/R组之间上述指标差异无统计学意义。与SAA+I/R组相比，SAA+si-DUSP2+I/R组p-ERK1/2表达增加，p-JNK表达减少；SAA+si-DUSP4+I/R组p-ERK表达下调，p-JNK表达上调。SAA通过抑制DUSP2介导的JNK去磷酸化和激活DUSP4/16介导的ERK1/2磷酸化来发挥抗心肌IRI的抗凋亡作用。
The purpose of this study was to observe the effects of salvianolic acid A (SAA) pretreatment on the myocardium during ischemia/reperfusion (I/R) and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP) 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI). Wistar rats were divided into the following six groups: control group (CON), I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R), PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R). The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum rate of ventricular pressure rise and fall (±dp/dtmax), myocardial infarction areas (MIA), lactate dehydrogenase (LDH), and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA-DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p-JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4+I/R group. SAA exerts an anti-apoptotic role against myocardial IRI by inhibiting DUSP2-mediated JNK dephosphorylation and activating DUSP4/16-mediated ERK1/2 phosphorylation.
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