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Article

Melatonin Alleviates Hypoxia-Induced Apoptosis of Granulosa Cells by Reducing ROS and Activating MTNR1B–PKA–Caspase8/9 Pathway

1
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
2
National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
3
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
*
Author to whom correspondence should be addressed.
Jing-Li Tao and Xuan Zhang contributed equally to this work.
Antioxidants 2021, 10(2), 184; https://doi.org/10.3390/antiox10020184
Received: 23 December 2020 / Revised: 23 January 2021 / Accepted: 25 January 2021 / Published: 28 January 2021
In mammalian ovaries, the avascular environment within follicular cavity is supposed to cause hypoxic status in granulosa cells (GCs), leading to apoptotic cell death accompanied by cumulative reactive oxygen species (ROS) production. Melatonin (N-acetyl-5-methoxytryptamine, MT), a broad-spectrum antioxidant that exists in porcine follicle fluid, was suggested to maintain GCs survival under stress conditions. In this study, using the established hypoxic model (1% O2) of cultured porcine GCs, we explored the effect of MT on GCs apoptosis. The results showed that MT restored cell viability and reduced the apoptosis of GCs during hypoxia exposure. In addition, GCs treated with MT exhibited decreased ROS levels and increased expression of antioxidant enzymes including heme oxygenase-1 (HO-1), glutathione S-transferase (GST), superoxide dismutase 1 (SOD1), and catalase (CAT) upon hypoxia incubation. Moreover, the hypoxia-induced expression of cleaved caspase 3, 8, and 9 was significantly inhibited after MT treatment. In contrast, blocking melatonin receptor 2 (MTNR1B) with a competitive antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT) diminished the inhibitory effects of MT on caspase 3 activation. By detecting levels of protein kinase (PKA), a downstream kinase of MTNR1B, we further confirmed the involvement of MT–MTNR1B signaling in mediating GCs protection during hypoxia stress. Together, the present data provide mechanistic evidence suggesting the role of MT in defending GCs from hypoxia-induced apoptosis. View Full-Text
Keywords: melatonin; hypoxia; granulosa cells; apoptosis; reactive oxygen species melatonin; hypoxia; granulosa cells; apoptosis; reactive oxygen species
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MDPI and ACS Style

Tao, J.-L.; Zhang, X.; Zhou, J.-Q.; Li, C.-Y.; Yang, M.-H.; Liu, Z.-J.; Zhang, L.-L.; Deng, S.-L.; Zhang, L.; Shen, M.; Liu, G.-S.; Liu, H.-L. Melatonin Alleviates Hypoxia-Induced Apoptosis of Granulosa Cells by Reducing ROS and Activating MTNR1B–PKA–Caspase8/9 Pathway. Antioxidants 2021, 10, 184. https://doi.org/10.3390/antiox10020184

AMA Style

Tao J-L, Zhang X, Zhou J-Q, Li C-Y, Yang M-H, Liu Z-J, Zhang L-L, Deng S-L, Zhang L, Shen M, Liu G-S, Liu H-L. Melatonin Alleviates Hypoxia-Induced Apoptosis of Granulosa Cells by Reducing ROS and Activating MTNR1B–PKA–Caspase8/9 Pathway. Antioxidants. 2021; 10(2):184. https://doi.org/10.3390/antiox10020184

Chicago/Turabian Style

Tao, Jing-Li, Xuan Zhang, Jia-Qi Zhou, Cheng-Yu Li, Ming-Hui Yang, Zhao-Jun Liu, Liang-Liang Zhang, Shou-Long Deng, Lu Zhang, Ming Shen, Guo-Shi Liu, and Hong-Lin Liu. 2021. "Melatonin Alleviates Hypoxia-Induced Apoptosis of Granulosa Cells by Reducing ROS and Activating MTNR1B–PKA–Caspase8/9 Pathway" Antioxidants 10, no. 2: 184. https://doi.org/10.3390/antiox10020184

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