Augmentation of leptin and hypoxia-inducible factor 1α mRNAs in the pre-eclamptic placenta

Iwagaki, Shigenori; Yokoyama, Yasuhiro; Tang, Lijun; Takahashi, Yuichiro; Nakagawa, Youji; Tamaya, Teruhiko

doi:10.1080/0951359042000196277

Cited by 36 publications

(36 citation statements)

References 36 publications

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“…Consistent with previous studies [27], we detected significantly higher HIF1α expression in placental tissues from patients with PE than in those from healthy pregnant women. HIF1α overexpression was also detected in the peripheral blood of patients with PE [28].…”

Section: Discussionsupporting

confidence: 92%

Enhancement of the HIF-1α/15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy

et al. 2014

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Preeclampsia (PE) is an extremely serious condition in pregnant women and the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiological factors of this disorder remain elusive. The increased release of 15-hydroxyeicosatetraenoic acid (15-HETE) in the placenta of preeclamptic patients has been studied, but its exact role in PE pathogenesis remains unknown. Mounting evidence shows that PE is associated with placental hypoxia, impaired placental angiogenesis, and endothelial dysfunction. In this study, we confirmed the upregulated expression of hypoxia-inducible factor 1α (HIF-1α) and 15-lipoxygenase-1/2 (15-LO-1/2) in patients with PE. Production of the arachidonic acid metabolite, 15-HETE, also increased in the preeclamptic placenta, which suggests enhanced activation of the HIF-1α–15-LO–15-HETE axis. Furthermore, this study is the first to show that the umbilical cord of preeclamptic women contains significantly higher serum concentrations of 15-HETE than that of healthy pregnant women. The results also show that expression of 15-LO-1/2 is upregulated in both human umbilical vein endothelial cells (HUVECs) collected from preeclamptic women and in those cultured under hypoxic conditions. Exogenous 15-HETE promotes the migration of HUVECs and in vitro tube formation and promotes cell cycle progression from the G0/G1 phase to the G2/M + S phase, whereas the 15-LO inhibitor, NDGA, suppresses these effects. The HIF-1α/15-LO/15-HETE pathway is therefore significantly associated within the pathology of PE.

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Section: Discussionsupporting

confidence: 92%

Enhancement of the HIF-1α/15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy

et al. 2014

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“…These effects may be of physiological relevance since trophoblastic cells are an important source of increased leptin production during pregnancy [23], [32]. Moreover, leptin levels are increased under stressful condition for placenta cells such as preeclampsia or gestational diabetes [32], [50]. This overproduction of leptin may be helpful to prevent the stress-mediated apoptosis of the trophoblastic cells.…”

Section: Discussionmentioning

confidence: 99%

Leptin Is an Anti-Apoptotic Effector in Placental Cells Involving p53 Downregulation

et al. 2014

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Leptin, a peripheral signal synthetized by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may work as an autocrine hormone. We have previously demonstrated that leptin promotes proliferation and survival of trophoblastic cells. In the present work, we aimed to study the molecular mechanisms that mediate the survival effect of leptin in placenta. We used the human placenta choriocarcinoma BeWo and first trimester Swan-71 cell lines, as well as human placental explants. We tested the late phase of apoptosis, triggered by serum deprivation, by studying the activation of Caspase-3 and DNA fragmentation. Recombinant human leptin added to BeWo cell line and human placental explants, showed a decrease on Caspase-3 activation. These effects were dose dependent. Maximal effect was achieved at 250 ng leptin/ml. Moreover, inhibition of endogenous leptin expression with 2 µM of an antisense oligonucleotide, reversed Caspase-3 diminution. We also found that the cleavage of Poly [ADP-ribose] polymerase-1 (PARP-1) was diminished in the presence of leptin. We analyzed the presence of low DNA fragments, products from apoptotic DNA cleavage. Placental explants cultivated in the absence of serum in the culture media increased the apoptotic cleavage of DNA and this effect was prevented by the addition of 100 ng leptin/ml. Taken together these results reinforce the survival effect exerted by leptin on placental cells. To improve the understanding of leptin mechanism in regulating the process of apoptosis we determined the expression of different intermediaries in the apoptosis cascade. We found that under serum deprivation conditions, leptin increased the anti-apoptotic BCL-2 protein expression, while downregulated the pro-apoptotic BAX and BID proteins expression in Swan-71 cells and placental explants. In both models leptin augmented BCL-2/BAX ratio. Moreover we have demonstrated that p53, one of the key cell cycle-signaling proteins, is downregulated in the presence of leptin under serum deprivation. On the other hand, we determined that leptin reduced the phosphorylation of Ser-46 p53 that plays a pivotal role for apoptotic signaling by p53. Our data suggest that the observed anti-apoptotic effect of leptin in placenta is in part mediated by the p53 pathway. In conclusion, we provide evidence that demonstrates that leptin is a trophic factor for trophoblastic cells.

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“…Both human (9,33) and rat (4,53) placentas have been shown to produce leptin as well express leptin receptors. Indeed, placental leptin gene and protein expressions are elevated in preeclampsia (18,22,31,48). However, it is unknown to what extent leptin derived from adipose and/or placental tissues is involved in pregnancyinduced hypertension.…”

Section: Discussionmentioning

confidence: 99%

Chronic hyperleptinemia results in the development of hypertension in pregnant rats

Palei

Spradley

Granger

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Despite the fact that obesity is a major risk factor for preeclampsia (PE), the pathophysiological mechanisms whereby obesity and metabolic factors such as leptin increase this risk are unclear. While human data have shown that hyperleptinemia is associated with PE, the long-term effect of hyperleptinemia on blood pressure during pregnancy is unknown. Thus we tested the hypothesis whether chronic circulating leptin elevations in pregnant rats increase blood pressure and placental factors known to play a role in PE. On gestational day (GD)14, rats were assigned to the normal pregnant group with food intake ad libitum (control), leptin-treated (0.5 μg·kg(-1)·min(-1) ip) pregnant group with food intake ad libitum (pregnant+LEP), and normal pregnant group with food intake adjusted to the food intake of pregnant+LEP rats (pregnant-FR). On GD19, mean arterial pressure (MAP) was assessed and tissues were collected. Serum leptin concentration was elevated in pregnant+LEP compared with control and pregnant-FR (18.0 ± 2.8 vs. 0.8 ± 0.1 vs. 0.3 ± 0.1 ng/ml; P < 0.05), which was associated with increased MAP (121.3 ± 8.1 vs. 102.4 ± 2.4 vs. 101.3 ± 1.8 mmHg; P < 0.05). Food intake and body weight were reduced in pregnant+LEP and pregnant-FR by the end of gestation. Additionally, placentas and fetuses of these groups were lighter than those of control. However, placental expression of tumor necrosis factor-α was significantly greater in pregnant+LEP compared with controls (1.6 ± 0.1 vs. 1.1 ± 0.1 pg/mg; P < 0.05). In conclusion, leptin increases blood pressure and placental tumor necrosis factor-α during pregnancy despite its effect of reducing food intake and body weight, and represents a mechanism whereby obesity can promote the development of hypertension in PE.

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Augmentation of leptin and hypoxia-inducible factor 1α mRNAs in the pre-eclamptic placenta

Cited by 36 publications

References 36 publications

Enhancement of the HIF-1α/15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy

Enhancement of the HIF-1α/15-LO/15-HETE Axis Promotes Hypoxia-Induced Endothelial Proliferation in Preeclamptic Pregnancy

Leptin Is an Anti-Apoptotic Effector in Placental Cells Involving p53 Downregulation

Chronic hyperleptinemia results in the development of hypertension in pregnant rats

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