Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1 |
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| Authors: | C Abán N Martinez C Carou I Albamonte A Toro A Seyahian A Franchi G Leguizamón D Trigubo A Damiano M Farina |
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| Institution: | 1.Laboratorio de Fisiopatología Placentaria, Centro de Estudios Farmacológicos y Botánicos (CEFYBO, CONICET), Facultad de Medicina,Universidad de Buenos Aires,Buenos Aires,Argentina;2.Laboratorio de Biología de la Reproducción, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO) - CONICET- Facultad de Medicina,Universidad de Buenos Aires,Buenos Aires,Argentina;3.Cátedra de Histología y Embriología, Facultad de Ciencias Veterinarias,UBA,Buenos Aires,Argentina;4.Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico – CEBBAD, Universidad Maimónides,Buenos Aires,Argentina;5.Departamento de Química Biológica, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Facultad de Ciencias Exactas y Naturales,UBA,Buenos Aires,Argentina;6.Laboratorio de Fisiopatología de la Pre?ez y el Parto, (CEFYBO, CONICET), Facultad de Medicina,UBA,Buenos Aires,Argentina;7.Departamento de Obstetricia y Ginecología, Unidad de Embarazo de Alto Riesgo,Centro de Educación Médica e Investigaciones Clínicas (CEMIC),Buenos Aires,Argentina;8.Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica,Universidad de Buenos Aires,Buenos Aires,Argentina |
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| Abstract: | During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process. |
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