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HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy
BACKGROUND: Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measur...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475713/ https://www.ncbi.nlm.nih.gov/pubmed/34320813 http://dx.doi.org/10.1161/JAHA.120.021069 |
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author | Yamamoto, Masahiro Hanatani, Shinsuke Araki, Satoshi Izumiya, Yasuhiro Yamada, Toshihiro Nakanishi, Nobuhiro Ishida, Toshifumi Yamamura, Satoru Kimura, Yuichi Arima, Yuichiro Nakamura, Taishi Takashio, Seiji Yamamoto, Eiichiro Sakamoto, Kenji Kaikita, Koichi Matsushita, Kenichi Morimoto, Sachio Ito, Takaaki Tsujita, Kenichi |
author_facet | Yamamoto, Masahiro Hanatani, Shinsuke Araki, Satoshi Izumiya, Yasuhiro Yamada, Toshihiro Nakanishi, Nobuhiro Ishida, Toshifumi Yamamura, Satoru Kimura, Yuichi Arima, Yuichiro Nakamura, Taishi Takashio, Seiji Yamamoto, Eiichiro Sakamoto, Kenji Kaikita, Koichi Matsushita, Kenichi Morimoto, Sachio Ito, Takaaki Tsujita, Kenichi |
author_sort | Yamamoto, Masahiro |
collection | PubMed |
description | BACKGROUND: Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. METHODS AND RESULTS: We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P<0.0001). Echocardiography showed that left ventricular end‐diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P<0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4‐transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis‐related genes, and this was accompanied by the activation of extracellular signal‐regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal‐regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. CONCLUSIONS: HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. REGISTRATION: URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr; Unique identifier: UMIN000043062. |
format | Online Article Text |
id | pubmed-8475713 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84757132021-10-01 HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy Yamamoto, Masahiro Hanatani, Shinsuke Araki, Satoshi Izumiya, Yasuhiro Yamada, Toshihiro Nakanishi, Nobuhiro Ishida, Toshifumi Yamamura, Satoru Kimura, Yuichi Arima, Yuichiro Nakamura, Taishi Takashio, Seiji Yamamoto, Eiichiro Sakamoto, Kenji Kaikita, Koichi Matsushita, Kenichi Morimoto, Sachio Ito, Takaaki Tsujita, Kenichi J Am Heart Assoc Original Research BACKGROUND: Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. METHODS AND RESULTS: We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P<0.0001). Echocardiography showed that left ventricular end‐diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P<0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4‐transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis‐related genes, and this was accompanied by the activation of extracellular signal‐regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal‐regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. CONCLUSIONS: HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. REGISTRATION: URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr; Unique identifier: UMIN000043062. John Wiley and Sons Inc. 2021-07-29 /pmc/articles/PMC8475713/ /pubmed/34320813 http://dx.doi.org/10.1161/JAHA.120.021069 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Yamamoto, Masahiro Hanatani, Shinsuke Araki, Satoshi Izumiya, Yasuhiro Yamada, Toshihiro Nakanishi, Nobuhiro Ishida, Toshifumi Yamamura, Satoru Kimura, Yuichi Arima, Yuichiro Nakamura, Taishi Takashio, Seiji Yamamoto, Eiichiro Sakamoto, Kenji Kaikita, Koichi Matsushita, Kenichi Morimoto, Sachio Ito, Takaaki Tsujita, Kenichi HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title | HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title_full | HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title_fullStr | HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title_full_unstemmed | HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title_short | HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy |
title_sort | he4 predicts progressive fibrosis and cardiovascular events in patients with dilated cardiomyopathy |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475713/ https://www.ncbi.nlm.nih.gov/pubmed/34320813 http://dx.doi.org/10.1161/JAHA.120.021069 |
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