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中华细胞与干细胞杂志(电子版) ›› 2021, Vol. 11 ›› Issue (05) : 284 -291. doi: 10.3877/cma.j.issn.2095-1221.2021.05.005

论著

circSERPINE2靶向miR-106b-5p对缺氧/复氧诱导的心肌细胞损伤的影响
魏薇1, 王文斌1,†(), 刘秀梅1   
  1. 1. 102600　北京市大兴区人民医院心内科
  • 收稿日期:2021-05-06 出版日期:2021-10-01
  • 通信作者: 王文斌
  • 基金资助:
    首都卫生发展科研项目(2020-3-7122)

Effects of circSERPINE2 targeting miR-106b-5p on cardiomyocyte damage induced by hypoxia /reoxygenation

wei Wei1, Wenbin Wang1,†(), Xiumei Liu1   

  1. 1. Department of Cardiology, Beijing Daxing District People’s Hospital, Beijing 102600, China
  • Received:2021-05-06 Published:2021-10-01
  • Corresponding author: Wenbin Wang
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引用本文：

魏薇, 王文斌, 刘秀梅. circSERPINE2靶向miR-106b-5p对缺氧/复氧诱导的心肌细胞损伤的影响[J/OL]. 中华细胞与干细胞杂志(电子版), 2021, 11(05): 284-291.

wei Wei, Wenbin Wang, Xiumei Liu. Effects of circSERPINE2 targeting miR-106b-5p on cardiomyocyte damage induced by hypoxia /reoxygenation[J/OL]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2021, 11(05): 284-291.

目的

探讨circSERPINE2对缺氧/复氧（H/R）诱导的心肌细胞损伤的影响及机制。

方法

体外培养大鼠心肌细胞H9c2，分为对照组（用常规培养基置于常规培养箱中培养7 h）、H/R组[无血清低糖DMEM培养基缺氧（不含氧）培养3 h后，10﹪ FBS的DMEM培养基复氧（19.95﹪氧）培养4 h]、H/R+pcDNA组（转染pcDNA至H9c2细胞后进行H/R处理）、H/R+pcDNA-circSERPINE2组（转染pcDNA-circSERPINE2至H9c2细胞后进行H/R处理）、H/ R+anti-miR-NC组（转染anti-miR-NC至H9c2细胞后进行H/R处理）、H/R+anti-miR- 106b- 5p组（转染anti-miR-106b-5p至H9c2细胞后进行H/R处理）、H/R+pcDNA- circSERPINE2+ miR-NC组（共转染pcDNA-circSERPINE2和miR-NC至H9c2细胞后进行H/R处理）和H/ R+pcDNA-circSERPINE2+miR-106b-5p组（共转染pcDNA- circSERPINE2和miR- 106b- 5p mimics至H9c2细胞后进行H/R处理）。用RT-qPCR法检测细胞中circSERPINE2和miR- 106b- 5p表达，流式细胞术检测细胞凋亡，免疫印迹法检测细胞中cleaved caspase-3和cleaved caspase-9蛋白表达，试剂盒检测细胞中MDA含量、SOD和GSH-Px活性。双荧光素酶报告基因实验检测circSERPINE2和miR-106b-5p调控关系。方差齐性，两组间比较用t检验；方差不齐，两组间比较用t’检验。

结果

与对照组比较，H/R组H9c2细胞中circSERPINE2表达（1.00±0.06比0.43±0.04）、SOD[（77.84±6.49）U/mL比（23.19±2.21） U/ mL]和GSH- Px活性[（59.21±5.31） U/mL比（17.62±1.53）U/mL]均降低，而miR-106b- 5p表达（1.00±0.07比2.66±0.23）、细胞凋亡率[（6.53±0.52）﹪比（24.21±2.18）﹪]、cleaved caspase-3（0.24±0.02比0.72±0.05）、cleaved caspase-9蛋白表达（0.13±0.02比0.65±0.04）和MDA含量[（5.23±0.47）nmol/L比（45.56±4.33）nmol/L]均升高，差异有统计学意义（P均< 0.05）。与H/R+pcDNA组比较，H/R+pcDNA-circSERPINE2组H9c2细胞凋亡率[（26.34±2.23）﹪比（10.08±0.81）﹪]、cleaved caspase-3 （0.75±0.05比0.32±0.04）和cleaved caspase-9蛋白表达（0.67±0.05比0.25±0.03）及MDA含量[（49.18±4.89） nmol/L比（6.79±0.59） nmol/L]均降低，而SOD[（21.42±2.03） U/ mL比（63.57±6.44）U/mL]和GSH-Px活性[（16.06±1.42） U/ mL比（47.94±5.52）U/mL]均升高，差异有统计学意义（P均< 0.05）。与H/R+anti-miR-NC组比较，H/R+anti-miR-106b-5p组H9c2细胞凋亡率[（26.23±2.15）﹪比(13.87±1.26）﹪]、cleaved caspase-3 （0.78±0.06比0.38±0.03）和cleaved caspase-9蛋白表达（0.68±0.05比0.31±0.03）及MDA含量[（48.38±4.21）nmol/L比（11.39± 1.42）nmol/L]均降低，而SOD[（22.19±2.21） U/ mL比（54.33±5.25）U/mL]和GSH- Px活性[（15.84±1.68） U/ mL比（40.42±3.51）U/ mL]均升高，差异有统计学意义（P均< 0.05）。circSERPINE2靶向结合并负调控miR-106b-5p表达。与H/R+pcDNA-circSERPINE2+miR-NC组比较，H/R+pcDNA- circSERPINE2+miR-106b-5p组H9c2细胞细胞凋亡率[（9.86±1.04）﹪比（18.47±1.24）﹪]、cleaved caspase-3 （0.31±0.03比0.66±0.04）、cleaved caspase-9蛋白表达（0.23±0.02比0.56±0.06）及MDA含量[（6.56±0.61）nmol/L比（36.97±3.14） nmol/ L，P < 0.05]均升高，而SOD[（64.14±6.32）U/ mL比（32.26±3.58）U/mL]和GSH-Px活性[（48.40±5.06）U/mL比（25.58±3.11）U/mL]均降低，差异有统计学意义（P均< 0.05）。

结论

上调circSERPINE2可抑制H/R诱导的大鼠心肌细胞凋亡及氧化应激反应，其作用机制可能通过靶向下调miR-106b-5p表达有关。

关键词: 心肌细胞, circRNA, miR-106b-5p, 细胞凋亡, 氧化应激
Objective

To investigate the effects of circSERPINE2 on hypoxia/reoxygenation (H/R) -induced cardiomyocyte damage and the mechanism.

Methods

Rat cardiomyocytes H9c2 were cultured in vitro and divided into control group (cells were cultured in a conventional incubator for 7 hours) H/R group (cells were cultured in serum-free low-glucose DMEM under hypoxia [no oxygen] for 3 hours, and then cultured in DMEM containing 10﹪ FBS under reoxygenation [19.95﹪ oxygen] for 4 hours) , H/R+pcDNA group (H9c2 cells transfected with pcDNA then treated by H/ R) , H/R+pcDNA-circSERPINE2 group (H9c2 cells transfected with pcDNA-circSERPINE2 then treated by H/R) , H/R+anti-miR-NC group (H9c2 cells transfected with anti-miR-NC then treated by H/R) , H/R+anti-miR-106b- 5p group (H9c2 cells transfected with anti-miR-106b-5p then treated by H/R) , H/R+pcDNA- circSERPINE2+miR- NC group (H9c2 cells co-transfected with pcDNA-circSERPINE2+miR-NC then treated by H/ R) and H/R+pcDNA- circSERPINE2+miR-106b-5p group (H9c2 cells transfected with pcDNA- circSERPINE2+miR-106b-5p then treated by H/R) . RT- qPCR was used to detect the expression of circSERPINE2 and miR-106b-5p. Flow cytometry was used to detect cell apoptosis. Western blotting was used to detect the protein expression of cleaved caspase-3 and cleaved caspase-9 in cells. The kits were used to detect the content of MDA and the activity of SOD and GSH-Px. The regulatory relationship between circSERPINE2 and miR- 106b- 5p was detected by dual luciferase reporter assay. The homogeneity of variance was compared between the two groups by t-test. The variance was uneven, and t' test was used.

Results

Compared with the control group, circSERPINE2 expression in H9c2 cells of H/R group was decreased (1.00±0.06 vs 0.43±0.04) , SOD[ (77.84±6.49) U/ mL vs (23.19±2.21) U/mL] and GSH-Px activity [ (59.21±5.31) U/mL vs (17.62±1.53) U/ mL] decreased, while miR-106b- 5p expression (1.00±0.07 vs 2.66±0.23) , apoptosis rate [ (6.53±0.52) ﹪ vs (24.21±2.18) ﹪], cleaved caspase-3 (0.24±0.02 vs 0.72± 0.05) and cleaved caspase-9 protein expression (0.13±0.02 vs 0.65±0.04) were increased. The content of MDA (5.23±0.47) nmol/L was higher than (45.56±4.33) nmol/L, and the difference was statistically significant (P < 0.05) . Compared with H/R + pcDNA group, the apoptosis rate of H9c2 cells [ (26.34±2.23) ﹪ vs (10.08±0.81) ﹪], cleaved caspase-3 (0.75±0.05 vs 0.32±0.04) , cleaved caspase-9 protein expression (0.67±0.05 vs 0.25±0.03) and MDA content [ (49.18±4.89) nmol/L vs (6.79±0.59) nmol/ L] in H/R + pcDNA-circSERPINE2 group were lower, However, SOD [ (21.42 ± 2.03) U/mL vs (63.57± 6.44) U/ mL] and GSH-Px activity [ (16.06 ± 1.42) U/ mL vs (47.94±5.52) U/mL] were increased, and the difference was statistically significant (P < 0.05) . Compared with H/R + anti-miR-NC group, the apoptosis rate of H9c2 cells[ (26.23± 2.15) ﹪ vs (13.87±1.26) ﹪], cleaved caspase- 3 (0.78±0.06 vs 0.38±0.03) , cleaved caspase-9 protein expression (0.68±0.05 vs 0.31±0.03) and MDA content [ (48.38±4.21) nmol/L vs (11.39±1.42) nmol/ L] in H/R + anti-miR-NC group were lower. However, SOD [ (22.19±2.21) U/ mL vs (54.33 ± 5.25) U/mL] and GSH- Px activity [ (15.84±1.68) U/mL vs (40.42±3.51) U/mL]were increased, and the difference was statistically significant (P < 0.05) . circSERPINE2 targeted and negatively regulated the expression of miR-106b-5p. Compared with the H/R+pcDNA-circSERPINE2+miR- NC group, the apoptosis rate [ (9.86±1.04) ﹪vs (18.47±1.24) ﹪], the protein expression of cleaved caspase-3 (0.31±0.03 vs 0.66±0.04) and cleaved caspase-9 (0.23±0.02 vs 0.56±0.06) , and the content of MDA [ (6.56±0.61) nmol/ L vs (36.97±3.14) nmol/L] of H9c2 cells in the H/ R+pcDNA-circSERPINE2+miR- 106b- 5p group were increased, but the SOD[ (64.14±6.32) U/ mL vs (32.26±3.58) U/mL] and GSH- Px activity [ (48.40±5.06) U/mL vs (25.58±3.11) U/mL] were decreased (P < 0.05) .

Conclusion

Up-regulation of circSERPINE2 can inhibit H/R-induced cardiomyocyte apoptosis and oxidative stress in rats, and its mechanism may be related to the targeted down-regulation of miR- 106b-5p expression.

Key words: Cardiomyocytes, circRNA, miR-106b-5p, Apoptosis, Oxidative stress
表1 引物序列信息
基因 序列 扩增长度（bp）
circSERPINE2 上游：CGGGAAATCCTATCAAGTGC 208
  下游：ATTGAAGTGGGAGCAGATGG  
GAPDH 上游：GAAAGCCTGCCGGTGACTAA 152
  下游：TTCCCGTTCTCAGCCTTGAC  
miR-106b-5p 上游：CAAGTACCCACAGTGCGGT 106
  下游：CTCGCTTCGGCAGCACA  
U6 上游：CTCGCTTCGGCAGCACA 94
  下游：AACGCTTCACGAATTTGCGT  
表2 circSERPINE2和miR-106b-5p在H/R诱导的心肌细胞中的表达（ ± s）
分组 实验次数 circSERPINE2 miR-106b-5p
对照 3 1.00±0.06 1.00±0.07
H/R 3 0.43±0.04 2.66±0.23
t'/t值   13.691 11.959
P值   < 0.001 < 0.001
图1 上调circSERPINE2后H/R诱导的心肌细胞中cleaved caspase-3和cleaved caspase-9蛋白表达
图2 上调circSERPINE2后H/R诱导的心肌细胞凋亡情况
表3 上调circSERPINE2对H/R诱导的心肌细胞损伤的影响（ ± s）
分组 实验次数 MDA（nmol/L） SOD（U/mL） GSH-Px（U/mL） 凋亡率（﹪） cleaved caspase-3蛋白 cleaved caspase-9蛋白
对照 3 5.23±0.47 77.84±6.49 59.21±5.31 6.53±0.52 0.24±0.02 0.13±0.02
H/R 3 45.56±4.33 23.19±2.21 17.62±1.53 24.21±2.18 0.72±0.05 0.65±0.04
t'/t值   16.038 13.806 13.036 13.664 15.438 20.140
P值   < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
H/R+pcDNA 3 49.18±4.89 21.42±2.03 16.06±1.42 26.34±2.23 0.75±0.05 0.67±0.05
H/R+pcDNA-circSERPINE2 3 6.79±0.59 63.57±6.44 47.94±5.52 10.08±0.81 0.32±0.04 0.25±0.03
t'/t值   14.907 10.812 9.688 10.870 11.632 12.476
P值   < 0.001 < 0.001 0.001 < 0.001 < 0.001 < 0.001
图3 circSERPINE2的序列中含有与miR-106b-5p互补的核苷酸序列
表4 双荧光素酶报告实验（ ± s）
分组 实验次数 WT-circSERPINE2
WT-circSERPINE2+miR-NC 3 1.00±0.06
WT-circSERPINE2+miR-106b-5p 3 0.42±0.05
t值   12.862
P值   < 0.001
MUT-circSERPINE2+miR-NC 3 0.98±0.05
MUT-circSERPINE2+miR-106b-5p 3 0.99±0.07
t值   0.201
P值   0.850
图4 下调miR-106b-5p对H/R诱导的心肌细胞凋亡的影响
表5 下调miR-106b-5p对H/R诱导的心肌细胞损伤的影响（ ± s）
分组 实验次数 MDA（nmol/L） SOD（U/mL） GSH-Px（U/mL） 凋亡率（﹪） cleaved caspase-3蛋白 cleaved caspase-9蛋白
H/R+anti-miR-NC 3 48.38±4.21 22.19±2.21 15.84±1.68 26.23±2.15 0.78±0.06 0.68±0.05
H/R+anti-miR-106b-5p 3 11.39±1.42 54.33±5.25 40.42±3.51 13.87±1.26 0.38±0.03 0.31±0.03
t'/t值   14.420 9.773 10.941 8.591 10.328 10.991
P值   < 0.001 0.001 < 0.001 0.001 < 0.001 < 0.001
图5 上调miR-106b-5p逆转上调circSERPINE2对H/R诱导的心肌细胞凋亡的作用
表6 上调miR-106b-5p逆转上调circSERPINE2对H/R诱导的心肌细胞损伤的作用（ ± s）
分组 实验次数 MDA （nmol/L） SOD （U/mL） GSH-Px（U/mL） 凋亡率（﹪） cleaved caspase-3蛋白 cleaved caspase-9蛋白
H/R+pcDNA-circSERPINE2+miR-NC 3 6.56±0.61 64.14±6.32 48.40±5.06 9.86±1.04 0.31±0.03 0.23±0.02
H/R+pcDNA-circSERPINE2+miR-106b-5p 3 36.97±3.14 32.26±3.58 25.58±3.11 18.47±1.24 0.66±0.04 0.56±0.06
t’/t值   16.467 7.602 6.655 9.215 12.124 9.037
P值   < 0.001 0.002 0.003 0.001 < 0.001 0.001
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