羟基红花黄色素A调控线粒体抗心肌缺血—再灌注损伤作用的实验研究
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摘要
目的：通过外科手术的方法建立大鼠心肌缺血再灌注损伤的模型，探讨HSYA抗心肌缺血-再灌注损伤的作用及机制。
方法：（1）外科手术的方法建立心肌缺血-再灌注损伤模型，并给予HSYA治疗；利用生物化学法分别检测血清CK、LDH、SOD和GSH-Px活力，血清MDA及组织匀浆H2O2和NO的含量；利用Fluo-3染色，流式细胞术检测细胞内钙离子浓度；分别利用Annexin Ⅴ-FITC凋亡检测试剂盒、流式细胞术和TUNEL法检测细胞凋亡；Western blotting检测LC3蛋白的表达，以LC3Ⅱ/LC3Ⅰ变化表示自噬。（2）Western blotting法检测线粒体和细胞浆中Cyt c表达；检测线粒体内缝隙连接蛋白Cx43的表达；检测心肌细胞中凋亡相关因子Bcl-2和Bax表达以及caspase-3的激活；检测心肌细胞内自噬相关蛋白Beclin1和Agt5的表达；检测PI3K-Akt信号通路中Akt的表达；以及利用ELISA检测组织匀浆中eNOS的表达。
结果：（1）心肌缺血-再灌注1h和24h，与假手术组比较，血清CK和LDH释放增加，血清MDA和组织匀浆中H2O2和NO的含量增加，血清SOD和GSH-Px活力降低，细胞内钙离子浓度显著增加；流式细胞术和TUNEL法结果均显示心肌细胞凋亡增加，而LC3Ⅱ/LC3Ⅰ比值增加，则暗示自噬增加，这些指标均以再灌注24h变化更明显；（2）Western blotting结果显示，心肌缺血-再灌注1h和24h，与假手术组比较，心肌细胞线粒体内Cyt c表达降低，而胞浆中Cyt c表达升高，心肌细胞中Bcl-2表达降低，Bax表达升高，且caspase-3被激活；心肌细胞中与钙离子调控相关的PMCA和SERCA表达均降低；缝隙连接蛋白Cx43表达降低；自噬相关蛋白Beclin1和Atg5表达增加，磷酸化的Akt和eNOS活性降低，而Akt表达变化不大，这些蛋白的表达以再灌注24h变化更明显。（3）心肌缺血-再灌注1h和24h模型大鼠经过HSYA治疗后，血清CK和LDH释放减少，血清MDA和组织匀浆中H2O2含量降低，血清SOD和GSH-Px活力增加，但是匀浆中NO含量增加，细胞中钙离子浓度降低，细胞凋亡和自噬降低；（4）Western blotting结果显示，心肌缺血-再灌注1h和24h模型大鼠经过HSYA治疗后，线粒体内Cyt c表达增加，而细胞浆中Cyt c表达降低，Bcl-2表达升高，Bax表达降低，caspase-3的激活被抑制，SERCA表达升高，而PMCA表达变化不明显，Beclin1和Atg5表达降低，磷酸化的Akt和eNOS活性升高，而Akt表达无明显变化。
结论：（1）心肌缺血-再灌注损伤导致大鼠血清CK和LDH释放增加，心肌细胞氧化损伤增强、抗氧化能力减弱、钙超载、凋亡和自噬增加，且以再灌注24h损伤更严重；（2）HSYA具有抗心肌缺血-再灌注损伤作用；（3）HSYA抗心肌缺血-再灌注引起的钙超载由SERCA调控，而非PMCA调控；（4）HSYA抗心肌缺血-再灌注损伤可能和升高Cx43表达，进而抑制细胞内活性氧的生成有关；（5）HSYA抑制心肌缺血-再灌注诱导细胞凋亡涉及到线粒体通路的激活，并可能由Bcl-2/Bax调控；（6）HSYA抑制心肌缺血-再灌注诱导细胞自噬可能通过其降低Beclin1和Agt5表达和激活pAkt-eNOS通路有关。
Objective：To construct rat models of myocardial ischemia-reperfusion injury bysurgical methods, and to explore the role and mechanism of HSYA anti-myocardialischemia-reperfusion injury.
Methods：(1) Rat models of myocardial ischemia-reperfusion injury wereestablished by surgical methods; using biochemical reagent kits to detect CK, LDH,SOD and GSH-Px activities, and the contents of MDA in serum, H2O2and NO;calcium concentration was measured by flow cytometry with fluo-3fluorescenceprobe; apoptosis was measured by TUNEL and flow cytometry double staining withAnnexin Ⅴ-FITC kits, respectively; LC3protein expression was measured withWestern blotting, LC3Ⅱ/LC3Ⅰindicated the autophagy;(2) Cyt c and gap junctionprotein in mitochondia, Cyt c in cytoplasma, apoptosis related proteins Bcl-2, Bax andcaspase-3in cells, autophagy related proteins Beclin1, Agt5and pAkt in cells, weremeasured by Western blotting assay, respectively; and eNOS in tissue homogenateswas measured by enzyme-linked immunosorbent assay (ELISA).
Results：(1) After myocardial ischemia-reperfusion lasting for1h and24h, ascompared with sham group, CK and LDH in serum release increased, the contents ofMDA in serum, H2O2and NO in tissue homogenates increased significantly, butSOD and GSH-Px activities in serum decreased, and calcium ion concentration incells increased significantly, resuls of flow cytometry and TUNEL assay showed thatapoptotic cells increased, and then, Western blotting result showed that LLC3Ⅱ/LC3Ⅰratio increased, it indicated autophagy increasing, these indicators were moreobvious in groups myocardial ischemia-reperfusion lasting for24h;(2) Aftermyocardial ischemia-reperfusion lasting for1h and24h, Western blotting resultsshowed, as compared with sham group, Cyt c expression in myocardial mitochondriareduced, and that in cytoplasma increased, and Bcl-2expression in cells decreased,but Bax expression increased, and caspase-3was activated; plasma membranedCa2+-ATPase (PMCA) and sarco/endoplasmic reticulum Ca2+ATPase (SERCA)expression decreased, autophagy related proteins of Beclin1and Atg5all increased,and phosphorylated Akt and eNOS activity all decreased, but Akt expression did not change obviously, the chages of these protein expressions was more obvious in24hgroup.(3) After HSYA treatment for myocardial ischemia-reperfusion model rats,serum CK and LDH release decreased, the contents of serum MDA and H2O2inhomogenates all decreased, serum SOD and GSH-Px all increased, but NO content inhomogenates increased, calcium ion concentration decreased in cells, apoptosis andautophagy all decreased.(4) Western blotting results showed that after HSYAtreatment for myocardial ischemia-reperfusion moded rats, mitochondrial Cyt cexpression increased, but cytoplasma Cyt c decreased, Bcl-2expression increased,Bax expression decreased, and caspase-3activation decreased, SERCA expressionincreased, but PMCA expression changes was not obvious, Beclin1and Atg5alldecreased, pAkt and eNOS all increased, but Akt did not showed obvious change.
Conclusion：(1) Myocardial ischemia-reperfusion injury can cause CK and LDHactivity increasing in serum, and enhance oxidative damage on myocardial cells,reduce antioxidant capability, induce calcium ion overload, increase apoptosis andautophagy, and it was more serious at24h of reperfusion injury.(2) HYSA can playagainst myocardial ischemia-reperfusion injury role by reducing these indicators asdecribed above;(3) HSYA can play role against calcium overload induced bymyocardial ischemia-reperfusion, and the role can be regulated by SERCA, but not byPMCA.(4) Anti-myocardial ischemia-reperfusion injury of HSYA may be related toreducing Cx43, thereby inhibiting the generation of reactive oxygen species in thecells.(5) The inhibitory effects of HSYA on apoptosis induced by myocardialischemia-reperfusion injury involved the activation of the mitochondrial pathway, andwas regulated by Bcl-2protein expression decreasing and Bax protein expressionincreasing;(6) The inhibitory effects of HSYA on autophagy induced by myocardialischemia-reperfusion injury was related to Beclin1and Agt5expression decreasingand activation of pAkt-eNOS pathway.
方法：（1）外科手术的方法建立心肌缺血-再灌注损伤模型，并给予HSYA治疗；利用生物化学法分别检测血清CK、LDH、SOD和GSH-Px活力，血清MDA及组织匀浆H2O2和NO的含量；利用Fluo-3染色，流式细胞术检测细胞内钙离子浓度；分别利用Annexin Ⅴ-FITC凋亡检测试剂盒、流式细胞术和TUNEL法检测细胞凋亡；Western blotting检测LC3蛋白的表达，以LC3Ⅱ/LC3Ⅰ变化表示自噬。（2）Western blotting法检测线粒体和细胞浆中Cyt c表达；检测线粒体内缝隙连接蛋白Cx43的表达；检测心肌细胞中凋亡相关因子Bcl-2和Bax表达以及caspase-3的激活；检测心肌细胞内自噬相关蛋白Beclin1和Agt5的表达；检测PI3K-Akt信号通路中Akt的表达；以及利用ELISA检测组织匀浆中eNOS的表达。
结果：（1）心肌缺血-再灌注1h和24h，与假手术组比较，血清CK和LDH释放增加，血清MDA和组织匀浆中H2O2和NO的含量增加，血清SOD和GSH-Px活力降低，细胞内钙离子浓度显著增加；流式细胞术和TUNEL法结果均显示心肌细胞凋亡增加，而LC3Ⅱ/LC3Ⅰ比值增加，则暗示自噬增加，这些指标均以再灌注24h变化更明显；（2）Western blotting结果显示，心肌缺血-再灌注1h和24h，与假手术组比较，心肌细胞线粒体内Cyt c表达降低，而胞浆中Cyt c表达升高，心肌细胞中Bcl-2表达降低，Bax表达升高，且caspase-3被激活；心肌细胞中与钙离子调控相关的PMCA和SERCA表达均降低；缝隙连接蛋白Cx43表达降低；自噬相关蛋白Beclin1和Atg5表达增加，磷酸化的Akt和eNOS活性降低，而Akt表达变化不大，这些蛋白的表达以再灌注24h变化更明显。（3）心肌缺血-再灌注1h和24h模型大鼠经过HSYA治疗后，血清CK和LDH释放减少，血清MDA和组织匀浆中H2O2含量降低，血清SOD和GSH-Px活力增加，但是匀浆中NO含量增加，细胞中钙离子浓度降低，细胞凋亡和自噬降低；（4）Western blotting结果显示，心肌缺血-再灌注1h和24h模型大鼠经过HSYA治疗后，线粒体内Cyt c表达增加，而细胞浆中Cyt c表达降低，Bcl-2表达升高，Bax表达降低，caspase-3的激活被抑制，SERCA表达升高，而PMCA表达变化不明显，Beclin1和Atg5表达降低，磷酸化的Akt和eNOS活性升高，而Akt表达无明显变化。
结论：（1）心肌缺血-再灌注损伤导致大鼠血清CK和LDH释放增加，心肌细胞氧化损伤增强、抗氧化能力减弱、钙超载、凋亡和自噬增加，且以再灌注24h损伤更严重；（2）HSYA具有抗心肌缺血-再灌注损伤作用；（3）HSYA抗心肌缺血-再灌注引起的钙超载由SERCA调控，而非PMCA调控；（4）HSYA抗心肌缺血-再灌注损伤可能和升高Cx43表达，进而抑制细胞内活性氧的生成有关；（5）HSYA抑制心肌缺血-再灌注诱导细胞凋亡涉及到线粒体通路的激活，并可能由Bcl-2/Bax调控；（6）HSYA抑制心肌缺血-再灌注诱导细胞自噬可能通过其降低Beclin1和Agt5表达和激活pAkt-eNOS通路有关。
Objective：To construct rat models of myocardial ischemia-reperfusion injury bysurgical methods, and to explore the role and mechanism of HSYA anti-myocardialischemia-reperfusion injury.
Methods：(1) Rat models of myocardial ischemia-reperfusion injury wereestablished by surgical methods; using biochemical reagent kits to detect CK, LDH,SOD and GSH-Px activities, and the contents of MDA in serum, H2O2and NO;calcium concentration was measured by flow cytometry with fluo-3fluorescenceprobe; apoptosis was measured by TUNEL and flow cytometry double staining withAnnexin Ⅴ-FITC kits, respectively; LC3protein expression was measured withWestern blotting, LC3Ⅱ/LC3Ⅰindicated the autophagy;(2) Cyt c and gap junctionprotein in mitochondia, Cyt c in cytoplasma, apoptosis related proteins Bcl-2, Bax andcaspase-3in cells, autophagy related proteins Beclin1, Agt5and pAkt in cells, weremeasured by Western blotting assay, respectively; and eNOS in tissue homogenateswas measured by enzyme-linked immunosorbent assay (ELISA).
Results：(1) After myocardial ischemia-reperfusion lasting for1h and24h, ascompared with sham group, CK and LDH in serum release increased, the contents ofMDA in serum, H2O2and NO in tissue homogenates increased significantly, butSOD and GSH-Px activities in serum decreased, and calcium ion concentration incells increased significantly, resuls of flow cytometry and TUNEL assay showed thatapoptotic cells increased, and then, Western blotting result showed that LLC3Ⅱ/LC3Ⅰratio increased, it indicated autophagy increasing, these indicators were moreobvious in groups myocardial ischemia-reperfusion lasting for24h;(2) Aftermyocardial ischemia-reperfusion lasting for1h and24h, Western blotting resultsshowed, as compared with sham group, Cyt c expression in myocardial mitochondriareduced, and that in cytoplasma increased, and Bcl-2expression in cells decreased,but Bax expression increased, and caspase-3was activated; plasma membranedCa2+-ATPase (PMCA) and sarco/endoplasmic reticulum Ca2+ATPase (SERCA)expression decreased, autophagy related proteins of Beclin1and Atg5all increased,and phosphorylated Akt and eNOS activity all decreased, but Akt expression did not change obviously, the chages of these protein expressions was more obvious in24hgroup.(3) After HSYA treatment for myocardial ischemia-reperfusion model rats,serum CK and LDH release decreased, the contents of serum MDA and H2O2inhomogenates all decreased, serum SOD and GSH-Px all increased, but NO content inhomogenates increased, calcium ion concentration decreased in cells, apoptosis andautophagy all decreased.(4) Western blotting results showed that after HSYAtreatment for myocardial ischemia-reperfusion moded rats, mitochondrial Cyt cexpression increased, but cytoplasma Cyt c decreased, Bcl-2expression increased,Bax expression decreased, and caspase-3activation decreased, SERCA expressionincreased, but PMCA expression changes was not obvious, Beclin1and Atg5alldecreased, pAkt and eNOS all increased, but Akt did not showed obvious change.
Conclusion：(1) Myocardial ischemia-reperfusion injury can cause CK and LDHactivity increasing in serum, and enhance oxidative damage on myocardial cells,reduce antioxidant capability, induce calcium ion overload, increase apoptosis andautophagy, and it was more serious at24h of reperfusion injury.(2) HYSA can playagainst myocardial ischemia-reperfusion injury role by reducing these indicators asdecribed above;(3) HSYA can play role against calcium overload induced bymyocardial ischemia-reperfusion, and the role can be regulated by SERCA, but not byPMCA.(4) Anti-myocardial ischemia-reperfusion injury of HSYA may be related toreducing Cx43, thereby inhibiting the generation of reactive oxygen species in thecells.(5) The inhibitory effects of HSYA on apoptosis induced by myocardialischemia-reperfusion injury involved the activation of the mitochondrial pathway, andwas regulated by Bcl-2protein expression decreasing and Bax protein expressionincreasing;(6) The inhibitory effects of HSYA on autophagy induced by myocardialischemia-reperfusion injury was related to Beclin1and Agt5expression decreasingand activation of pAkt-eNOS pathway.
引文
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