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Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension

OBJECTIVE: Pulmonary hypertension (PH) is characterized with pulmonary vasoconstriction and vascular remodeling mediated by 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) according to our previous studies. Meanwhile, telomerase reverse transcriptase (TERT) activity is highly corre...

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Autores principales: Shen, Tingting, Ma, Jun, Zhang, Lei, Yu, Xiufeng, Liu, Mengmeng, Hou, Yunlong, Wang, Yanyan, Ma, Cui, Li, Shuzhen, Zhu, Daling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871619/
https://www.ncbi.nlm.nih.gov/pubmed/24376652
http://dx.doi.org/10.1371/journal.pone.0083132
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author Shen, Tingting
Ma, Jun
Zhang, Lei
Yu, Xiufeng
Liu, Mengmeng
Hou, Yunlong
Wang, Yanyan
Ma, Cui
Li, Shuzhen
Zhu, Daling
author_facet Shen, Tingting
Ma, Jun
Zhang, Lei
Yu, Xiufeng
Liu, Mengmeng
Hou, Yunlong
Wang, Yanyan
Ma, Cui
Li, Shuzhen
Zhu, Daling
author_sort Shen, Tingting
collection PubMed
description OBJECTIVE: Pulmonary hypertension (PH) is characterized with pulmonary vasoconstriction and vascular remodeling mediated by 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) according to our previous studies. Meanwhile, telomerase reverse transcriptase (TERT) activity is highly correlated with vascular injury and remodeling, suggesting that TERT may be an essential determinant in the development of PH. The aim of this study was to determine the contribution and molecular mechanisms of TERT in the pathogenesis of PH. APPROACH AND RESULTS: We measured the right ventricular systolic pressure (RVSP) and ventricular weight, analyzed morphometric change of the pulmonary vessels in the hypoxia or monocrotaline treated rats. Bromodeoxyuridine incorporation, transwell assay and flow cytometry in pulmonary smooth muscle cells were performed to investigate the roles and relationship of TERT and 15-LO/15-HETE in PH. We revealed that the expression of TERT was increased in pulmonary vasculature of patients with PH and in the monocrotaline or hypoxia rat model of PH. The up-regulation of TERT was associated with experimental elevated RVSP and pulmonary vascular remodeling. Coimmunoprecipitation experiments identified TERT as a novel interacting partner of 15-LO-2. TERT and 15-LO-2 augmented protein expression of each other. In addition, the proliferation, migration and cell-cycle transition from G(0)/G(1) phase to S phase induced by hypoxia were inhibited by TERT knockdown, which were rescued by 15-HETE addition. CONCLUSIONS: These results demonstrate that TERT regulates pulmonary vascular remodeling. TERT and 15-LO-2 form a positive feedback loop and together promote proliferation and migration of pulmonary artery smooth muscle cells, creating a self-amplifying circuit which propels pulmonary hypertension.
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spelling pubmed-38716192013-12-27 Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension Shen, Tingting Ma, Jun Zhang, Lei Yu, Xiufeng Liu, Mengmeng Hou, Yunlong Wang, Yanyan Ma, Cui Li, Shuzhen Zhu, Daling PLoS One Research Article OBJECTIVE: Pulmonary hypertension (PH) is characterized with pulmonary vasoconstriction and vascular remodeling mediated by 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) according to our previous studies. Meanwhile, telomerase reverse transcriptase (TERT) activity is highly correlated with vascular injury and remodeling, suggesting that TERT may be an essential determinant in the development of PH. The aim of this study was to determine the contribution and molecular mechanisms of TERT in the pathogenesis of PH. APPROACH AND RESULTS: We measured the right ventricular systolic pressure (RVSP) and ventricular weight, analyzed morphometric change of the pulmonary vessels in the hypoxia or monocrotaline treated rats. Bromodeoxyuridine incorporation, transwell assay and flow cytometry in pulmonary smooth muscle cells were performed to investigate the roles and relationship of TERT and 15-LO/15-HETE in PH. We revealed that the expression of TERT was increased in pulmonary vasculature of patients with PH and in the monocrotaline or hypoxia rat model of PH. The up-regulation of TERT was associated with experimental elevated RVSP and pulmonary vascular remodeling. Coimmunoprecipitation experiments identified TERT as a novel interacting partner of 15-LO-2. TERT and 15-LO-2 augmented protein expression of each other. In addition, the proliferation, migration and cell-cycle transition from G(0)/G(1) phase to S phase induced by hypoxia were inhibited by TERT knockdown, which were rescued by 15-HETE addition. CONCLUSIONS: These results demonstrate that TERT regulates pulmonary vascular remodeling. TERT and 15-LO-2 form a positive feedback loop and together promote proliferation and migration of pulmonary artery smooth muscle cells, creating a self-amplifying circuit which propels pulmonary hypertension. Public Library of Science 2013-12-23 /pmc/articles/PMC3871619/ /pubmed/24376652 http://dx.doi.org/10.1371/journal.pone.0083132 Text en © 2013 Shen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shen, Tingting
Ma, Jun
Zhang, Lei
Yu, Xiufeng
Liu, Mengmeng
Hou, Yunlong
Wang, Yanyan
Ma, Cui
Li, Shuzhen
Zhu, Daling
Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title_full Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title_fullStr Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title_full_unstemmed Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title_short Positive Feedback-Loop of Telomerase Reverse Transcriptase and 15-Lipoxygenase-2 Promotes Pulmonary Hypertension
title_sort positive feedback-loop of telomerase reverse transcriptase and 15-lipoxygenase-2 promotes pulmonary hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871619/
https://www.ncbi.nlm.nih.gov/pubmed/24376652
http://dx.doi.org/10.1371/journal.pone.0083132
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