Wang Min, Sun Gui-Bo, Zhang Jing-Yi, Luo Yun, Yu Ying-Li, Xu Xu-Dong, Meng Xiang-Bao, Zhang Miao-di, Lin Wen-Bin, Sun Xiao-Bo
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
Int J Cardiol. 2015 Apr 15;185:167-76. doi: 10.1016/j.ijcard.2015.03.140. Epub 2015 Mar 12.
We have previously shown that Elatoside C reduces cardiomyocyte apoptosis during ischaemia/reperfusion (I/R). Here, we investigated whether Elatoside C improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in Elatoside C-induced protection.
Isolated rat hearts were subjected to global ischaemia followed by reperfusion in the absence or presence of Elatoside C. We found that Elatoside C significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Consistently, Elatoside C prevented I/R-induced mitochondrial dysfunction, which was evident by the inhibition of mitochondrial ROS production, mitochondrial permeability transition pore (mPTP) opening, cytochrome c release from the mitochondria and Bax translocation. Moreover, Elatoside C improved abnormal calcium handling during I/R, including increasing sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) activity, alleviating [Ca(2+)]ER depletion, and reducing the expression levels of ER stress protein markers. All of these protective effects of Elatoside C were partially abolished by the PI3K/Akt inhibitor LY294002, ERK1/2 inhibitor PD98059, and JAK2/STAT3 inhibitor AG490. Further assessment in isolated cardiomyocytes showed that Elatoside C maintained the Ca(2+) transients and cell shortening against I/R.
Elatoside C protects against cardiac injury during I/R by attenuating oxidative stress and [Ca(2+)]i overload through the activation of both the reperfusion injury salvage kinase (RISK) pathway (including PI3K/Akt and ERK1/2) and the survivor activating factor enhancement (SAFE) pathway (including JAK2/STAT3) and, subsequently, inhibiting the opening of mPTPs.
我们之前已经表明，紫丁香苷C可减少缺血/再灌注（I/R）期间的心肌细胞凋亡。在此，我们研究了紫丁香苷C是否能改善I/R处理的离体大鼠心脏的心脏功能，并阐明了紫丁香苷C诱导保护作用的潜在机制。
离体大鼠心脏在有无紫丁香苷C的情况下进行全心缺血后再灌注。我们发现紫丁香苷C显著减轻了I/R诱导的心脏功能障碍并抑制了氧化应激。同样，紫丁香苷C预防了I/R诱导的线粒体功能障碍，这通过抑制线粒体活性氧生成、线粒体通透性转换孔（mPTP）开放、细胞色素c从线粒体释放以及Bax易位得以体现。此外，紫丁香苷C改善了I/R期间异常的钙处理，包括增加肌浆网Ca(2+)ATP酶（SERCA2）活性、减轻[Ca(2+)]内质网耗竭以及降低内质网应激蛋白标志物的表达水平。紫丁香苷C的所有这些保护作用均被PI3K/Akt抑制剂LY294002、ERK1/2抑制剂PD98059和JAK2/STAT3抑制剂AG490部分消除。在离体心肌细胞中的进一步评估表明，紫丁香苷C维持了Ca(2+)瞬变并抵抗I/R引起的细胞缩短。
紫丁香苷C通过激活再灌注损伤挽救激酶（RISK）途径（包括PI3K/Akt和ERK1/2）和存活激活因子增强（SAFE）途径（包括JAK2/STAT3）减轻氧化应激和[Ca(2+)]i过载，随后抑制mPTP开放，从而保护心脏免受I/R损伤。
