title: Anandamide oxidative metabolism-induced endoplasmic reticulum stress and apoptosis.
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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Almada
authors.affiliation: 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. brunofonseca@ff.up.pt.
authors.forename: B M
authors.initials: BM
authors.lastname: Fonseca
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Amaral
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Diniz-da-Costa
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Correia-da-Silva
authors.affiliation: 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.
authors.forename: N
authors.initials: N
authors.lastname: Teixeira
mesh_terms: D017209:Apoptosis; D001095:Arachidonic Acids / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D063388:Endocannabinoids / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C078814:anandamide
keywords: Anandamide; Apoptosis; Human endometrial stromal cells