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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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