title: Leptin reduces apoptosis triggered by high temperature in human placental villous explants: The role of the p53 pathway.
abstract: Maternal fever is common during pregnancy and has for many years been suspected to harm the developing fetus. Whether increased maternal temperature produces exaggerated apoptosis in trophoblast cells remains unclear. Since p53 is a critical regulator of apoptosis we hypothesized that increased temperature in placenta produces abnormal expression of proteins in the p53 pathway and finally caspase-3 activation. Moreover, leptin, produced by placenta, is known to promote the proliferation and survival of trophoblastic cells. Thus, we aimed to study the possible role of leptin preventing apoptosis triggered by high temperature, as well as the molecular mechanisms underlying this effect. Fresh placental tissue was collected from normal pregnancies. Explants of placental villi were exposed to 37 °C, 40 °C and 42 °C during 3 h in the presence or absence of 10 nM leptin in DMEM-F12 medium. Western blotting and qRT-PCR was performed to analyze the expression of p53 and downstream effector, P53AIP1, Mdm2, p21, BAX and BCL-2 as well as the activated cleaved form of caspase-3 and the fragment of cytokeratin-18 (CK-18) cleaved at Asp396 (neoepitope M30). Phosphorylation of the Ser 46 residue on p53, the expression of P53AIP1, Mdm2, p21, as well as caspase-3 and CK-18 were significantly increased in explants at 40 °C and 42 °C. Conversely, these effects were significantly attenuated by leptin 10 nM at both 40 °C and 42 °C. The BCL2/BAX ratio was also significantly decreased in explants at 40 °C and 42 °C compared with explants incubated at 37 °C, which was prevented by leptin stimulation. These data illustrate the potential role of leptin for reducing apoptosis in trophoblast explants, including trophoblastic cells, triggered by high temperature, by preventing the activation of p53 signaling.
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, Virgen Macarena University Hospital, University of Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pérez-Pérez
authors.affiliation: Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Ayelén R
authors.initials: AR
authors.lastname: Toro
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, Virgen Macarena University Hospital, University of Seville, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Vilarino-Garcia
authors.affiliation: Department of Obstetrics and Gynecology, Virgen Macarena University Hospital, University of Seville, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Guadix
authors.affiliation: Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Julieta L
authors.initials: JL
authors.lastname: Maymó
authors.affiliation: Department of Obstetrics and Gynecology, Virgen Macarena University Hospital, University of Seville, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Dueñas
authors.affiliation: Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Varone
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, Virgen Macarena University Hospital, University of Seville, Spain. Electronic address: margalet@us.es.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sánchez-Margalet
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002824:Chorionic Villi / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006358:Hot Temperature; D006801:Humans; D053538:Keratin-18 / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D053538:Keratin-18; D020738:Leptin; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3
keywords: Apoptosis; CK-18(M30); Leptin; P53; Placenta; Temperature