Cargando…
Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways
BACKGROUND: Hypoxia induces cell apoptosis in the uterosacral ligaments of patients with pelvic organ prolapse by upregulation of hypoxia-inducible factor-1α (HIF-1α). This study aimed to investigate the effects of HIF-1α on human uterosacral ligament fibroblasts (hUSLFs) following treatment with th...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Scientific Literature, Inc.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289032/ https://www.ncbi.nlm.nih.gov/pubmed/30504760 http://dx.doi.org/10.12659/MSM.913384 |
_version_ | 1783379912774647808 |
---|---|
author | Zhao, Xinrui Liu, Lidong Li, Rui Wei, Xuan Luan, Wenqing Liu, Peishu Zhao, Jing |
author_facet | Zhao, Xinrui Liu, Lidong Li, Rui Wei, Xuan Luan, Wenqing Liu, Peishu Zhao, Jing |
author_sort | Zhao, Xinrui |
collection | PubMed |
description | BACKGROUND: Hypoxia induces cell apoptosis in the uterosacral ligaments of patients with pelvic organ prolapse by upregulation of hypoxia-inducible factor-1α (HIF-1α). This study aimed to investigate the effects of HIF-1α on human uterosacral ligament fibroblasts (hUSLFs) following treatment with the chemical inducer of hypoxia, cobalt chloride (CoCl(2)), and to explore the underlying mechanisms. MATERIAL/METHODS: Ten women who underwent hysterectomy for benign disease provided uterosacral ligament tissue for cell extraction. Following CoCl(2) treatment, cell viability of isolated and cultured hUSLFs was evaluated by the MTT assay. JC-1 fluorescence mitochondrial imaging was used to study the change in mitochondrial membrane potential. Cell apoptosis and expression of apoptosis-associated proteins and collagen type I alpha 1 (COL1A1) were measured by flow cytometry, TUNEL and Western blot, respectively. RESULTS: Hypoxia increased the expression of HIF-1α and increased cell apoptosis, decreased cell viability and expression levels of COL1A1. The JC-1 assay showed that the mitochondrial membrane potential was reduced and caspase-8, and -9 inhibitors partly reduced hUSLF apoptosis. HIF-1α treatment downregulated the expression of cellular FLICE inhibitory protein (c-FLIP), decoy receptor 2 (DcR2), and the ratio of Bcl-2 to Bax, and upregulated the expression tumor necrosis factor related apoptosis-inducing ligand (TRAIL), death receptor 5 (DR5) or TRAIL-R2, Fas, Bcl-2 interacting protein 3 (BNIP3), and cytochrome C, and increased the activation of caspase-3, caspase-8, and caspase-9, all of which were reversed by knockdown of HIF-1α. CONCLUSIONS: HIF-1α significantly induced apoptosis of hUSLFs through both the cell death receptor and the mitochondrial-associated apoptosis pathways. |
format | Online Article Text |
id | pubmed-6289032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | International Scientific Literature, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62890322018-12-28 Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways Zhao, Xinrui Liu, Lidong Li, Rui Wei, Xuan Luan, Wenqing Liu, Peishu Zhao, Jing Med Sci Monit Lab/In Vitro Research BACKGROUND: Hypoxia induces cell apoptosis in the uterosacral ligaments of patients with pelvic organ prolapse by upregulation of hypoxia-inducible factor-1α (HIF-1α). This study aimed to investigate the effects of HIF-1α on human uterosacral ligament fibroblasts (hUSLFs) following treatment with the chemical inducer of hypoxia, cobalt chloride (CoCl(2)), and to explore the underlying mechanisms. MATERIAL/METHODS: Ten women who underwent hysterectomy for benign disease provided uterosacral ligament tissue for cell extraction. Following CoCl(2) treatment, cell viability of isolated and cultured hUSLFs was evaluated by the MTT assay. JC-1 fluorescence mitochondrial imaging was used to study the change in mitochondrial membrane potential. Cell apoptosis and expression of apoptosis-associated proteins and collagen type I alpha 1 (COL1A1) were measured by flow cytometry, TUNEL and Western blot, respectively. RESULTS: Hypoxia increased the expression of HIF-1α and increased cell apoptosis, decreased cell viability and expression levels of COL1A1. The JC-1 assay showed that the mitochondrial membrane potential was reduced and caspase-8, and -9 inhibitors partly reduced hUSLF apoptosis. HIF-1α treatment downregulated the expression of cellular FLICE inhibitory protein (c-FLIP), decoy receptor 2 (DcR2), and the ratio of Bcl-2 to Bax, and upregulated the expression tumor necrosis factor related apoptosis-inducing ligand (TRAIL), death receptor 5 (DR5) or TRAIL-R2, Fas, Bcl-2 interacting protein 3 (BNIP3), and cytochrome C, and increased the activation of caspase-3, caspase-8, and caspase-9, all of which were reversed by knockdown of HIF-1α. CONCLUSIONS: HIF-1α significantly induced apoptosis of hUSLFs through both the cell death receptor and the mitochondrial-associated apoptosis pathways. International Scientific Literature, Inc. 2018-12-02 /pmc/articles/PMC6289032/ /pubmed/30504760 http://dx.doi.org/10.12659/MSM.913384 Text en © Med Sci Monit, 2018 This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) ) |
spellingShingle | Lab/In Vitro Research Zhao, Xinrui Liu, Lidong Li, Rui Wei, Xuan Luan, Wenqing Liu, Peishu Zhao, Jing Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title | Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title_full | Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title_fullStr | Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title_full_unstemmed | Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title_short | Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways |
title_sort | hypoxia-inducible factor 1-α (hif-1α) induces apoptosis of human uterosacral ligament fibroblasts through the death receptor and mitochondrial pathways |
topic | Lab/In Vitro Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289032/ https://www.ncbi.nlm.nih.gov/pubmed/30504760 http://dx.doi.org/10.12659/MSM.913384 |
work_keys_str_mv | AT zhaoxinrui hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT liulidong hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT lirui hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT weixuan hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT luanwenqing hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT liupeishu hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways AT zhaojing hypoxiainduciblefactor1ahif1ainducesapoptosisofhumanuterosacralligamentfibroblaststhroughthedeathreceptorandmitochondrialpathways |