Effects of ginkgolide B on Caspase-3/PTEN/Akt pathway and cell proliferation and apoptosis in hypoxia/reoxygenation cardiomyocytes_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHEN Haiyu ¹ , ZHENG Fuzhen ¹ , WENG Guoxing ¹ , BAO Jiayin ¹ , HUANG Jie ¹ , YAN Licheng ¹ ,  KE Qiuqing ²

1. Department of Cardiovascular Surgery, Provincial Clinical School of Medicine, Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, P. R. China;
2. Department of Internal Medicine, Provincial Clinical School of Medicine, Fujian Medical University, Fujian Provincial Jinshan Hospital, Fuzhou, 350001, P. R. China;

Corresponding?author：

KE Qiuqing, Email: 9315217@qq.com

Keywords：

Ginkgolide B; hypoxia/reoxygenation; cardiomyocyte; Caspase-3/PTEN/Akt pathway; cell proliferation; cell apoptosis

DOI：

10.7507/1007-4848.202109047

Video：

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Objective To investigate the effect of ginkgolide B (GB) on cysteinyl aspartate specific proteinase-3 (Caspase-3)/chromosome 10 deletion phosphatase-tension protein homologue (PTEN)/protein kinase B (Akt) pathway and cell proliferation and apoptosis in hypoxia/reoxygenation cardiomyocytes. Methods H9C2 cells were cultured in vitro. A control group was cultured in serum-free DMEM high glucose medium at 37°C and 5% CO₂ for 28 hours. The remaining groups were prepared with hypoxia/reoxygenation models. A GB low-dose group and a GB high-dose group were treated with GB pretreatment with final concentration of 50 μmol/L and 200 μmol/L respectively at 1 h before hypoxia/reoxygenation. A carvedilol group was treated with carvedilol of a final concentration of 10 μmol/L at 1 h before hypoxia/reoxygenation. The proliferation and apoptosis of H9C2 cells were detected, and the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), reactive oxygen species (ROS), PTEN, Akt, phosphorylated Akt (p-Akt) and Caspase-3 in H9C2 cells were also detected. Results Compared with the control group, the proliferation rate of H9C2 cell, and the levels of PTEN, Akt and p-Akt in other groups decreased, and the apoptosis rate, and the levels of LDH, MDA, ROS and Caspase-3 increased (P<0.05). Compared with the hypoxia/reoxygenation group, the proliferation rate of H9C2 cell, and the levels of PTEN, Akt and p-Akt in all GB dose groups and the carvedilol group increased; the apoptosis rate, and the levels of LDH, MDA, ROS and Caspase-3 decreased, and the effect of GB was in a dose dependent manner; however, the effect of GB was not as strong as carvedilol (P<0.05). Conclusion GB can inhibit H9C2 cell apoptosis and promote H9C2 cell proliferation by activating Caspase-3/PTEN/Akt pathway.

Citation： CHEN Haiyu, ZHENG Fuzhen, WENG Guoxing, BAO Jiayin, HUANG Jie, YAN Licheng, KE Qiuqing. Effects of ginkgolide B on Caspase-3/PTEN/Akt pathway and cell proliferation and apoptosis in hypoxia/reoxygenation cardiomyocytes. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2022, 29(12): 1647-1652. doi: 10.7507/1007-4848.202109047 Copy

1.	陳小蘭, 顏安華, 鄭道國. 二甲雙胍通過調控PARP-1活性對心肌梗死大鼠模型發揮保護作用. 中國藥師, 2019, 22(8): 1401-1406.
2.	高啟軍, 董曉帆, 鄧長金. 心肌缺血再灌注損傷研究進展. 嶺南心血管病雜志, 2020, 26(1): 107-109.
3.	Li MY, Chang CT, Han YT, et al. Ginkgolide B promotes neuronal differentiation through the Wnt/β-catenin pathway in neural stem cells of the postnatal mammalian subventricular zone. Sci Rep, 2018, 8(1): 14947.
4.	Dai Y, Zhang H, Zhang J, et al. Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway. Chem Biol Interact, 2018, 284: 32-40.
5.	Song N, Zhang T, Xu X, et al. miR-21 protects against ischemia/reperfusion-induced acute kidney injury by preventing epithelial cell apoptosis and inhibiting dendritic cell maturation. Front Physiol, 2018, 9: 790.
6.	Chen YX, Zhu DY, Gao J, et al. Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3β/β-catenin axis. FEBS J, 2019, 286(6): 1101-1119.
7.	杜東輝, 王艷, 許小冰, 等. 高表達miR-132-3p間充質干細胞外泌體對缺氧/復氧受損腦微血管內皮細胞功能的改善作用. 中國腦血管病雜志, 2018, 15(11): 584-591.
8.	張旭, 陳旺盛, 馮健, 等. 銀杏內酯B保護缺氧/復氧誘導心肌細胞損傷模型的作用及機制. 中國組織工程研究, 2019, 23(19): 3097-3101.
9.	趙勇, 徐巖, 姬婷婷. 卡維地洛預處理對缺氧/復氧誘導心肌H9C2細胞凋亡的影響及其機制. 山東醫藥, 2019, 59(35): 20-23.
10.	陳亦晨, 孫良紅, 李小攀, 等. 2002—2018年上海市浦東新區居民缺血性心臟病死亡特征及減壽率分析. 中國全科醫學, 2020, 23(18): 2242-2248.
11.	張美香, 章鳴. TLR4在心肌缺血再灌注損傷中作用的研究進展. 現代免疫學, 2019, 39(3): 237-240.
12.	張曉紅, 時景璞. 缺氧誘導因子-1調控缺氧狀態下心肌細胞自噬和凋亡的研究進展. 中國胸心血管外科臨床雜志, 2020, 27(9): 1087-1093.
13.	蘇琦, 趙娜, 苗雨欣, 等. 銀杏內酯B抗心肌氧化應激損傷作用機制研究. 中國中醫基礎醫學雜志, 2019, 25(7): 918-921.
14.	Wu Y, Yao J, Feng K. miR-124-5p/NOX2 axis modulates the ROS production and the inflammatory microenvironment to protect against the cerebral I/R injury. Neurochem Res, 2020, 45(2): 404-417.
15.	孫旭暉, 陳四華. 卡維地洛聯合螺內酯對慢性心力衰竭患者心肌重塑的影響及機制. 中國臨床藥理學雜志, 2019, 35(20): 2535-2538.
16.	Nezamoleslami S, Sheibani M, Jahanshahi F, et al. Protective effect of dapsone against renal ischemia-reperfusion injury in rat. Immunopharmacol Immunotoxicol, 2020, 42(3): 272-279.
17.	Zhao Q, Liu Z, Huang B, et al. PEDF improves cardiac function in rats subjected to myocardial ischemia/reperfusion injury by inhibiting ROS generation via PEDF-R. Int J Mol Med, 2018, 41(6): 3243-3252.
18.	Pandey P, Sayyed U, Tiwari RK, et al. Hesperidin induces ROS-mediated apoptosis along with cell cycle arrest at G2/M phase in human gall bladder carcinoma. Nutr Cancer, 2019, 71(4): 676-687.
19.	Katifelis H, Lyberopoulou A, Mukha I, et al. Ag/Au bimetallic nanoparticles induce apoptosis in human cancer cell lines via P53, CASPASE-3 and BAX/BCL-2 pathways. Artif Cells Nanomed Biotechnol, 2018, 46(sup3): S389-S398.
20.	Li G, Song Y, Li G, et al. Downregulation of microRNA-21 expression inhibits proliferation, and induces G1 arrest and apoptosis via the PTEN/AKT pathway in SKM-1 cells. Mol Med Rep, 2018, 18(3): 2771-2779.
21.	Pan H, Li T, Jiang Y, et al. Overexpression of circular RNA ciRS-7 abrogates the tumor suppressive effect of miR-7 on gastric cancer via PTEN/PI3K/AKT signaling pathway. J Cell Biochem, 2018, 119(1): 440-446.
22.	Diao MY, Zhu Y, Yang J, et al. Hypothermia protects neurons against ischemia/reperfusion-induced pyroptosis via m6A-mediated activation of PTEN and the PI3K/Akt/GSK-3β signaling pathway. Brain Res Bull, 2020, 159: 25-31.
23.	Jin M, Li C, Zhang Q, et al. Effects of aspirin on proliferation, invasion and apoptosis of Hep-2 cells via the PTEN/AKT/NF-κB/survivin signaling pathway. Oncol Lett, 2018, 15(6): 8454-8460.
24.	Wu X, Liang Y, Jing X, et al. Rifampicin prevents SH-SY5Y cells from rotenone-induced apoptosis via the PI3K/Akt/GSK-3β/CREB signaling pathway. Neurochem Res, 2018, 43(4): 886-893.
25.	Wang S, Zhu Y, Qiu R. Shikonin protects H9C2 cardiomyocytes against hypoxia/reoxygenation injury through activation of PI3K/Akt signaling pathway. Biomed Pharmacother, 2018, 104: 712-717.

1. 陳小蘭, 顏安華, 鄭道國. 二甲雙胍通過調控PARP-1活性對心肌梗死大鼠模型發揮保護作用. 中國藥師, 2019, 22(8): 1401-1406.
2. 高啟軍, 董曉帆, 鄧長金. 心肌缺血再灌注損傷研究進展. 嶺南心血管病雜志, 2020, 26(1): 107-109.
3. Li MY, Chang CT, Han YT, et al. Ginkgolide B promotes neuronal differentiation through the Wnt/β-catenin pathway in neural stem cells of the postnatal mammalian subventricular zone. Sci Rep, 2018, 8(1): 14947.
4. Dai Y, Zhang H, Zhang J, et al. Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway. Chem Biol Interact, 2018, 284: 32-40.
5. Song N, Zhang T, Xu X, et al. miR-21 protects against ischemia/reperfusion-induced acute kidney injury by preventing epithelial cell apoptosis and inhibiting dendritic cell maturation. Front Physiol, 2018, 9: 790.
6. Chen YX, Zhu DY, Gao J, et al. Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3β/β-catenin axis. FEBS J, 2019, 286(6): 1101-1119.
7. 杜東輝, 王艷, 許小冰, 等. 高表達miR-132-3p間充質干細胞外泌體對缺氧/復氧受損腦微血管內皮細胞功能的改善作用. 中國腦血管病雜志, 2018, 15(11): 584-591.
8. 張旭, 陳旺盛, 馮健, 等. 銀杏內酯B保護缺氧/復氧誘導心肌細胞損傷模型的作用及機制. 中國組織工程研究, 2019, 23(19): 3097-3101.
9. 趙勇, 徐巖, 姬婷婷. 卡維地洛預處理對缺氧/復氧誘導心肌H9C2細胞凋亡的影響及其機制. 山東醫藥, 2019, 59(35): 20-23.
10. 陳亦晨, 孫良紅, 李小攀, 等. 2002—2018年上海市浦東新區居民缺血性心臟病死亡特征及減壽率分析. 中國全科醫學, 2020, 23(18): 2242-2248.
11. 張美香, 章鳴. TLR4在心肌缺血再灌注損傷中作用的研究進展. 現代免疫學, 2019, 39(3): 237-240.
12. 張曉紅, 時景璞. 缺氧誘導因子-1調控缺氧狀態下心肌細胞自噬和凋亡的研究進展. 中國胸心血管外科臨床雜志, 2020, 27(9): 1087-1093.
13. 蘇琦, 趙娜, 苗雨欣, 等. 銀杏內酯B抗心肌氧化應激損傷作用機制研究. 中國中醫基礎醫學雜志, 2019, 25(7): 918-921.
14. Wu Y, Yao J, Feng K. miR-124-5p/NOX2 axis modulates the ROS production and the inflammatory microenvironment to protect against the cerebral I/R injury. Neurochem Res, 2020, 45(2): 404-417.
15. 孫旭暉, 陳四華. 卡維地洛聯合螺內酯對慢性心力衰竭患者心肌重塑的影響及機制. 中國臨床藥理學雜志, 2019, 35(20): 2535-2538.
16. Nezamoleslami S, Sheibani M, Jahanshahi F, et al. Protective effect of dapsone against renal ischemia-reperfusion injury in rat. Immunopharmacol Immunotoxicol, 2020, 42(3): 272-279.
17. Zhao Q, Liu Z, Huang B, et al. PEDF improves cardiac function in rats subjected to myocardial ischemia/reperfusion injury by inhibiting ROS generation via PEDF-R. Int J Mol Med, 2018, 41(6): 3243-3252.
18. Pandey P, Sayyed U, Tiwari RK, et al. Hesperidin induces ROS-mediated apoptosis along with cell cycle arrest at G2/M phase in human gall bladder carcinoma. Nutr Cancer, 2019, 71(4): 676-687.
19. Katifelis H, Lyberopoulou A, Mukha I, et al. Ag/Au bimetallic nanoparticles induce apoptosis in human cancer cell lines via P53, CASPASE-3 and BAX/BCL-2 pathways. Artif Cells Nanomed Biotechnol, 2018, 46(sup3): S389-S398.
20. Li G, Song Y, Li G, et al. Downregulation of microRNA-21 expression inhibits proliferation, and induces G1 arrest and apoptosis via the PTEN/AKT pathway in SKM-1 cells. Mol Med Rep, 2018, 18(3): 2771-2779.
21. Pan H, Li T, Jiang Y, et al. Overexpression of circular RNA ciRS-7 abrogates the tumor suppressive effect of miR-7 on gastric cancer via PTEN/PI3K/AKT signaling pathway. J Cell Biochem, 2018, 119(1): 440-446.
22. Diao MY, Zhu Y, Yang J, et al. Hypothermia protects neurons against ischemia/reperfusion-induced pyroptosis via m6A-mediated activation of PTEN and the PI3K/Akt/GSK-3β signaling pathway. Brain Res Bull, 2020, 159: 25-31.
23. Jin M, Li C, Zhang Q, et al. Effects of aspirin on proliferation, invasion and apoptosis of Hep-2 cells via the PTEN/AKT/NF-κB/survivin signaling pathway. Oncol Lett, 2018, 15(6): 8454-8460.
24. Wu X, Liang Y, Jing X, et al. Rifampicin prevents SH-SY5Y cells from rotenone-induced apoptosis via the PI3K/Akt/GSK-3β/CREB signaling pathway. Neurochem Res, 2018, 43(4): 886-893.
25. Wang S, Zhu Y, Qiu R. Shikonin protects H9C2 cardiomyocytes against hypoxia/reoxygenation injury through activation of PI3K/Akt signaling pathway. Biomed Pharmacother, 2018, 104: 712-717.

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