scholarly journals Cigarette Smoke Extract Activates Hypoxia-Inducible Factors in a Reactive Oxygen Species-Dependent Manner in Stroma Cells from Human Endometrium

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 48
Author(s):  
Naoko Kida ◽  
Yoshiyuki Matsuo ◽  
Yoshiko Hashimoto ◽  
Kenichiro Nishi ◽  
Tomoko Tsuzuki-Nakao ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stromal Cells ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Human Endometrium ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Endometrial Stromal Cells ◽  
Hypoxic Conditions

Cigarette smoking (CS) is a major contributing factor in the development of a large number of fatal and debilitating disorders, including degenerative diseases and cancers. Smoking and passive smoking also affect the establishment and maintenance of pregnancy. However, to the best of our knowledge, the effects of smoking on the human endometrium remain poorly understood. In this study, we investigated the regulatory mechanism underlying CS-induced hypoxia-inducible factor (HIF)-1α activation using primary human endometrial stromal cells and an immortalized cell line (KC02-44D). We found that the CS extract (CSE) increased reactive oxygen species levels and stimulated HIF-1α protein stabilization in endometrial stromal cells, and that CS-induced HIF-1α-dependent gene expression under non-hypoxic conditions in a concentration- and time-dependent manner. Additionally, we revealed the upregulated expression of a hypoxia-induced gene set following the CSE treatment, even under normoxic conditions. These results indicated that HIF-1α might play an important role in CS-exposure-induced cellular stress, inflammation, and endometrial remodeling.

scholarly journals Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species

2010 ◽  
Vol 21 (18) ◽  
pp. 3247-3257 ◽  
Author(s):  
David A. Patten ◽  
Véronique N. Lafleur ◽  
Geneviève A. Robitaille ◽  
Denise A. Chan ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Complex Iii ◽  
Oxygen Species ◽  
Ang Ii ◽  
Hypoxia Inducible Factor 1

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22phox siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1–dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase–generated ROS in Ang II–mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

scholarly journals NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 730-740 ◽  
Author(s):  
Marwa Al-Sabbagh ◽  
Luca Fusi ◽  
Jenny Higham ◽  
Yun Lee ◽  
Kaiyu Lei ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Stromal Cells ◽  
Rho Gtpase ◽  
Primary Cultures ◽  
Reactive Oxygen ◽  
Marker Genes ◽  
Oxygen Species ◽  
Endometrial Stromal Cells ◽  
Decidual Cells

Abstract Differentiation of human endometrial stromal cells into specialized decidual cells is critical for embryo implantation and survival of the conceptus. Initiation of this differentiation process is strictly dependent on elevated cAMP levels, but the signal intermediates that control the expression of decidual marker genes, such as prolactin (PRL) and IGFBP1, remain poorly characterized. Here we show that cAMP-dependent decidualization can be attenuated or enhanced upon treatment of primary cultures with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenylen iodonium) or activator (apocynin), respectively. Time-course analysis demonstrated that cAMP enhances endogenous reactive oxygen species production, apparent after 12 h of stimulation, which coincides with a dramatic increase in decidual PRL and IGFBP1 expression. Knockdown of the Rho GTPase RAC1, which disables activation of the NADPH oxidase homologs NADPH oxidase (NOX)-1, NOX-2, and NOX-3, had no effect on PRL or IGFBP1 expression. In contrast, silencing of NOX-4, or its cofactor p22PHOX, inhibited the expression of both decidual markers. Finally, we show that the NOX-4/p22PHOX complex regulates the DNA-binding activity of CCAAT/enhancer binding protein-β, a key regulator of human endometrial stromal cell differentiation. Thus, NOX-4 activation and reactive oxygen species signaling play an integral role in initiating the endometrial decidual response in preparation of pregnancy.

scholarly journals HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Reproduction ◽  
2015 ◽  
Vol 149 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Ronit Yalu ◽  
Adepeju Esther Oyesiji ◽  
Iris Eisenberg ◽  
Tal Imbar ◽  
Rina Meidan
Keyword(s):  
Reactive Oxygen Species ◽  
Mrna Expression ◽  
Granulosa Cells ◽  
Time Window ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Protein Levels ◽  
Concomitant Reduction

Hypoxia-inducible factor 1 alpha (HIF1A) and endothelin 2 (EDN2) are transiently expressed during the same time window in the developing corpus luteum (CL). In this study, we sought to investigate the involvement of LH/cAMP, reactive oxygen species (ROS), and a hypoxia-mimetic compound (CoCl2) on HIF1A expression and how it affected EDN2 levels, using transformed human granulosa cells (thGCs) and primary bovine granulosa cells (GCs). CoCl2 elevated HIF1A protein levels in thGCs in a dose-dependent manner. Forskolin alone had no significant effect; however, forskolin and CoCl2 together further induced HIF1A protein and EDN2 mRNA expression in thGCs. Similarly, in primary GCs, LH with CoCl2 synergistically augmented HIF1A protein levels, which resulted in higher expression of EDN2 and another well-known hypoxia-inducible gene, VEGF (VEGFA). Importantly, LH alone elevated HIF1A mRNA but not its protein. The successful knockdown of HIF1A in thGCs using siRNA abolished hypoxia-induced EDN2 and also the additive effect of forskolin and CoCl2. We then examined the roles of ROS in thGCs: hydrogen peroxide (20 and 50 μM) elevated HIF1A protein as well as the expression of EDN2, implying that induction of HIF1A protein levels is sufficient to stimulate the expression of EDN2 (and VEGF) in normoxia. A broad-range ROS scavenger, butylated hydroxyanisole, inhibited CoCl2-induced HIF1A protein with a concomitant reduction in the mRNA expression of EDN2 and VEGF in thGCs. The results obtained in this study suggest that HIF1A, induced by various stimuli, is an essential mediator of EDN2 mRNA expression. The results may also explain the rise in the levels of HIF1A-dependent genes (EDN2 and VEGF) in the developing CL.

scholarly journals Reactive oxygen species stimulate prostaglandin F2α production in human endometrial stromal cells in vitro

2001 ◽  
Vol 16 (9) ◽  
pp. 1797-1801 ◽  
Author(s):  
Norihiro Sugino ◽  
Ayako Karube-Harada ◽  
Shiro Kashida ◽  
Shuji Takiguchi ◽  
Hiroshi Kato
Keyword(s):  
Reactive Oxygen Species ◽  
Stromal Cells ◽  
Reactive Oxygen ◽  
Prostaglandin F2α ◽  
Oxygen Species ◽  
Endometrial Stromal Cells

scholarly journals Anti-Tumor Drug-Loaded Oxygen Nanobubbles for the Degradation of HIF-1α and the Upregulation of Reactive Oxygen Species in Tumor Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1464 ◽  
Author(s):  
Muhammad Saad Khan ◽  
Jangsun Hwang ◽  
Kyungwoo Lee ◽  
Yonghyun Choi ◽  
Youngmin Seo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Drug Delivery ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Oxygen Species ◽  
Tumor Resistance ◽  
Therapeutic Modalities ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions

Hypoxia is a key concern during the treatment of tumors, and hypoxia-inducible factor 1 alpha (HIF-1α) has been associated with increased tumor resistance to therapeutic modalities. In this study, doxorubicin-loaded oxygen nanobubbles (Dox/ONBs) were synthesized, and the effectiveness of drug delivery to MDA-MB-231 breast cancer and HeLa cells was evaluated. Dox/ONBs were characterized using optical and fluorescence microscopy, and size measurements were performed through nanoparticle tracking analysis (NTA). The working mechanism of Dox was evaluated using reactive oxygen species (ROS) assays, and cellular penetration was assessed with confocal microscopy. Hypoxic conditions were established to assess the effect of Dox/ONBs under hypoxic conditions compared with normoxic conditions. Our results indicate that Dox/ONBs are effective for drug delivery, enhancing oxygen levels, and ROS generation in tumor-derived cell lines.

Hypoxic but not anoxic stabilization of HIF-1α requires mitochondrial reactive oxygen species

2002 ◽  
Vol 283 (5) ◽  
pp. L922-L931 ◽  
Author(s):  
Clara Schroedl ◽  
David S. McClintock ◽  
G. R. Scott Budinger ◽  
Navdeep S. Chandel
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
A549 Cells ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Oxygen Species ◽  
Protein Levels ◽  
Transport Chain ◽  
Ht1080 Cells

The molecular mechanisms by which cells detect hypoxia (1.5% O2), resulting in the stabilization of hypoxia-inducible factor 1α (HIF-1α) protein remain unclear. One model proposes that mitochondrial generation of reactive oxygen species is required to stabilize HIF-1α protein. Primary evidence for this model comes from the observation that cells treated with complex I inhibitors, such as rotenone, or cells that lack mitochondrial DNA (ρ0-cells) fail to generate reactive oxygen species or stabilize HIF-1α protein in response to hypoxia. In the present study, we investigated the role of mitochondria in regulating HIF-1α protein stabilization under anoxia (0% O2). Wild-type A549 and HT1080 cells stabilized HIF-1α protein in response to hypoxia and anoxia. The ρ0-A549 cells and ρ0-HT1080 cells failed to accumulate HIF-1α protein in response to hypoxia. However, both ρ0-A549 and ρ0-HT1080 were able to stabilize HIF-1α protein levels in response to anoxia. Rotenone inhibited hypoxic, but not anoxic, stabilization of HIF-1α protein. These results indicate that a functional electron transport chain is required for hypoxic but not anoxic stabilization of HIF-1α protein.

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