Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress
Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress
复制标题
小檗碱通过激活 JAK2/STAT3 信号传导和减弱内质网应激来保护大鼠心脏免受缺血/再灌注损伤。
DOI：
10.1038/aps.2015.136
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发表时间：
2016-03-01
影响因子：
8.2
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Zhao, Guo-long;Yu, Li-ming;Wang, Yun
目的：黄连中的一种异喹啉生物碱黄连素(berberine，BBR)具有心脏保护作用。由于内质网应激在心肌缺血/再灌注(MI/R)诱导的细胞凋亡中起着关键作用，因此研究BBR在MI/R损伤过程中是否通过调节内质网应激水平起到保护作用，并明确这一过程中的信号机制。方法：雄性大鼠给予BBR(200 mg·kg(-1)·d(-1)，ig)2周，然后进行MI/R手术。心脏大小和功能通过超声心动图进行评估。检测心肌梗死面积和细胞凋亡率。测定血清总LDH水平和心肌组织中CK活性、超氧化物歧化产物、丙二醛含量和抗氧化性超氧化物歧化酶活性。体外培养的大鼠胚胎心肌细胞H9C2暴露于模拟缺血/再灌流(SIR)。免疫印迹法检测心肌细胞凋亡、内质网应激相关蛋白及信号转导蛋白的表达。结果：BBR可显著缩小心肌梗死面积，改善心功能，抑制心肌细胞凋亡和氧化损伤。此外，BBR可抑制MI/R诱导的内质网应激，下调心肌组织中PERK和eIF2α的磷酸化水平以及ATF4和CHOP的表达。BBR还激活了心肌组织中JAK2/STAT3信号通路，与JAK2/STAT3特异性抑制剂AG490共同处理不仅可阻断BBR的保护作用，还可阻断BBR对MI/R诱导的ER应激的抑制作用。在H9C2细胞中，BBR(50mU·mol/L)可明显减少SIR诱导的细胞凋亡、氧化应激和内质网应激。结论：BBR通过激活AK2/STAT3信号通路，减轻ER应激诱导的细胞凋亡，从而减轻大鼠的MI/R损伤。
Aim: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process.Methods: Male rats were treated with BBR (200 mg.kg(-1).d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses.Results: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2 alpha and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 mu mol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA.Conclusion: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.