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Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase

Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antag...

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Autores principales: Oe, Yuji, Ko, Mieko, Fushima, Tomofumi, Sato, Emiko, Karumanchi, S. Ananth, Sato, Hiroshi, Sugawara, Junichi, Ito, Sadayoshi, Takahashi, Nobuyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758763/
https://www.ncbi.nlm.nih.gov/pubmed/29311569
http://dx.doi.org/10.1038/s41598-017-18260-7
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author Oe, Yuji
Ko, Mieko
Fushima, Tomofumi
Sato, Emiko
Karumanchi, S. Ananth
Sato, Hiroshi
Sugawara, Junichi
Ito, Sadayoshi
Takahashi, Nobuyuki
author_facet Oe, Yuji
Ko, Mieko
Fushima, Tomofumi
Sato, Emiko
Karumanchi, S. Ananth
Sato, Hiroshi
Sugawara, Junichi
Ito, Sadayoshi
Takahashi, Nobuyuki
author_sort Oe, Yuji
collection PubMed
description Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. eNOS polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of eNOS gene product. We first overexpressed sFlt1 using adenovirus in eNOS (−/−) and eNOS (+/+) mice. Excessive sFlt1 and lack of eNOS synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of eNOS in the presence of excess sFlt1 also induced thrombocytopenia, whereas eNOS (+/+) mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of eNOS synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states.
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spelling pubmed-57587632018-01-10 Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase Oe, Yuji Ko, Mieko Fushima, Tomofumi Sato, Emiko Karumanchi, S. Ananth Sato, Hiroshi Sugawara, Junichi Ito, Sadayoshi Takahashi, Nobuyuki Sci Rep Article Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. eNOS polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of eNOS gene product. We first overexpressed sFlt1 using adenovirus in eNOS (−/−) and eNOS (+/+) mice. Excessive sFlt1 and lack of eNOS synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of eNOS in the presence of excess sFlt1 also induced thrombocytopenia, whereas eNOS (+/+) mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of eNOS synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states. Nature Publishing Group UK 2018-01-08 /pmc/articles/PMC5758763/ /pubmed/29311569 http://dx.doi.org/10.1038/s41598-017-18260-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Oe, Yuji
Ko, Mieko
Fushima, Tomofumi
Sato, Emiko
Karumanchi, S. Ananth
Sato, Hiroshi
Sugawara, Junichi
Ito, Sadayoshi
Takahashi, Nobuyuki
Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title_full Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title_fullStr Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title_full_unstemmed Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title_short Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase
title_sort hepatic dysfunction and thrombocytopenia induced by excess sflt1 in mice lacking endothelial nitric oxide synthase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758763/
https://www.ncbi.nlm.nih.gov/pubmed/29311569
http://dx.doi.org/10.1038/s41598-017-18260-7
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