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Anandamide oxidative metabolism-induced endoplasmic reticulum stress and apoptosis

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Abstract

The Endocannabinoid System (ECS) has been recognized as a crucial player in human reproduction. Changes in the levels of anandamide (AEA), the main endocannabinoid (eCB), negatively affect reproductive events, such as implantation, decidualization and placentation. Cyclooxygenase-2 (COX-2) is a major enzyme expressed in the endometrium and its involvement in female reproductive system has evolved over the last few years. Currently, COX-2 oxidative metabolism is emerging as a key mediator of AEA-induced actions. In this study, we aimed to disclose the mechanisms underlying the effects of AEA in human endometrial stromal cell fate, using a human-derived endometrial cell line (St-T1b). We found that AEA has an anti-proliferative activity through a direct effect on cell cycle progression by inducing G2/M arrest. Moreover, high levels of AEA increased COX-2 activity, triggering apoptotic cell death, with loss of mitochondrial membrane potential, induction of caspase -9 and -3/-7 activities, and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, the involvement of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress was verified. These effects were prevented by pre-incubation with a selective COX-2 inhibitor. Therefore, we hypothesize that, in response to altered levels of this eCB, COX-2 oxidative metabolism of AEA may deregulate endometrial cell turnover and, consequently, interfere with cellular events crucial for implantation and decidualization, with a negative impact on human fertility.

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Acknowledgements

The authors thank Fundação para a Ciência e Tecnologia (FCT) for the grant attributed to Almada M (SFRH/BD/81561/2011), Fonseca BM (SFRH/BPD/72958/2010) and Cristina Amaral (SFRH/BPD/98304/2013). The authors also thank to Joana Macedo for helping with the graphic design.

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Authors and Affiliations

  1. UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313, Porto, Portugal

    M. Almada, B. M. Fonseca, C. Amaral, M. Diniz-da-Costa, G. Correia-da-Silva & N. Teixeira

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  1. M. Almada
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  2. B. M. Fonseca
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  3. C. Amaral
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  4. M. Diniz-da-Costa
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  5. G. Correia-da-Silva
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  6. N. Teixeira
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Correspondence to B. M. Fonseca.

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Almada, M., Fonseca, B.M., Amaral, C. et al. Anandamide oxidative metabolism-induced endoplasmic reticulum stress and apoptosis. Apoptosis 22, 816–826 (2017). https://doi.org/10.1007/s10495-017-1356-4

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