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Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction

Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological fa...

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Autores principales: Tsuda, Takuma, Takefuji, Mikito, Wettschureck, Nina, Kotani, Kazuhiko, Morimoto, Ryota, Okumura, Takahiro, Kaur, Harmandeep, Eguchi, Shunsuke, Sakaguchi, Teruhiro, Ishihama, Sohta, Kikuchi, Ryosuke, Unno, Kazumasa, Matsushita, Kunihiro, Ishikawa, Shizukiyo, Offermanns, Stefan, Murohara, Toyoaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502432/
https://www.ncbi.nlm.nih.gov/pubmed/28550160
http://dx.doi.org/10.1084/jem.20161924
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author Tsuda, Takuma
Takefuji, Mikito
Wettschureck, Nina
Kotani, Kazuhiko
Morimoto, Ryota
Okumura, Takahiro
Kaur, Harmandeep
Eguchi, Shunsuke
Sakaguchi, Teruhiro
Ishihama, Sohta
Kikuchi, Ryosuke
Unno, Kazumasa
Matsushita, Kunihiro
Ishikawa, Shizukiyo
Offermanns, Stefan
Murohara, Toyoaki
author_facet Tsuda, Takuma
Takefuji, Mikito
Wettschureck, Nina
Kotani, Kazuhiko
Morimoto, Ryota
Okumura, Takahiro
Kaur, Harmandeep
Eguchi, Shunsuke
Sakaguchi, Teruhiro
Ishihama, Sohta
Kikuchi, Ryosuke
Unno, Kazumasa
Matsushita, Kunihiro
Ishikawa, Shizukiyo
Offermanns, Stefan
Murohara, Toyoaki
author_sort Tsuda, Takuma
collection PubMed
description Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein–coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3′-5′-cyclic adenosine monophosphate (cAMP)–dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.
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spelling pubmed-55024322018-01-03 Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction Tsuda, Takuma Takefuji, Mikito Wettschureck, Nina Kotani, Kazuhiko Morimoto, Ryota Okumura, Takahiro Kaur, Harmandeep Eguchi, Shunsuke Sakaguchi, Teruhiro Ishihama, Sohta Kikuchi, Ryosuke Unno, Kazumasa Matsushita, Kunihiro Ishikawa, Shizukiyo Offermanns, Stefan Murohara, Toyoaki J Exp Med Research Articles Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein–coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3′-5′-cyclic adenosine monophosphate (cAMP)–dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure. The Rockefeller University Press 2017-07-03 /pmc/articles/PMC5502432/ /pubmed/28550160 http://dx.doi.org/10.1084/jem.20161924 Text en © 2017 Tsuda et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Tsuda, Takuma
Takefuji, Mikito
Wettschureck, Nina
Kotani, Kazuhiko
Morimoto, Ryota
Okumura, Takahiro
Kaur, Harmandeep
Eguchi, Shunsuke
Sakaguchi, Teruhiro
Ishihama, Sohta
Kikuchi, Ryosuke
Unno, Kazumasa
Matsushita, Kunihiro
Ishikawa, Shizukiyo
Offermanns, Stefan
Murohara, Toyoaki
Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title_full Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title_fullStr Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title_full_unstemmed Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title_short Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
title_sort corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502432/
https://www.ncbi.nlm.nih.gov/pubmed/28550160
http://dx.doi.org/10.1084/jem.20161924
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