Leptin reduces apoptosis triggered by high temperature in human placental villous explants: The role of the p53 pathway

ANTONIO PÉREZ PÉREZ; AYELÉN TORO; PILAR GUADIX; JULIETA L. MAYMÓ; JOSÉ DUEÑAS; CECILIA L. VARONE; VÍCTOR SÁNCHEZ-MARGALET

PLACENTA

W B SAUNDERS CO LTD

Lugar: Londres; Año: 2016 vol. 42 p. 106 - 113

0143-4004

Maternal fever is common during pregnancy and has for many years been suspected to harm thedeveloping fetus. Whether increased maternal temperature produces exaggerated apoptosis in trophoblastcells remains unclear. Since p53 is a critical regulator of apoptosis we hypothesized that increasedtemperature in placenta produces abnormal expression of proteins in the p53 pathway and finallycaspase-3 activation. Moreover, leptin, produced by placenta, is known to promote the proliferation andsurvival of trophoblastic cells. Thus, we aimed to study the possible role of leptin preventing apoptosistriggered 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 exposedto 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 fragmentof 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 ascaspase-3 and CK-18 were significantly increased in explants at 40 C and 42 C. Conversely, these effectswere significantly attenuated by leptin 10 nM at both 40 C and 42 C. The BCL2/BAX ratio was alsosignificantly decreased in explants at 40 C and 42 C compared with explants incubated at 37 C, whichwas 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 p53signaling.