Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction

Takuma Tsuda, Mikito Takefuji, Nina Wettschureck, Kazuhiko Kotani, Ryota Morimoto, Takahiro Okumura, Harmandeep Kaur, Shunsuke Eguchi, Teruhiro Sakaguchi, Sohta Ishihama, Ryosuke Kikuchi, Kazumasa Unno, Kunihiro Matsushita, Shizukiyo Ishikawa, Stefan Offermanns, Toyoaki Murohara

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1877-1888
Number of pages12
JournalJournal of Experimental Medicine
Volume214
Issue number7
DOIs
StatePublished - Jul 1 2017

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Corticotropin-Releasing Hormone Receptors
Heart Failure
Urocortins
Cardiac Myocytes
G-Protein-Coupled Receptors
Cyclic AMP
Stroke Volume
Perfusion
Hormones
Pressure
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Tsuda, T., Takefuji, M., Wettschureck, N., Kotani, K., Morimoto, R., Okumura, T., ... Murohara, T. (2017). Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction. Journal of Experimental Medicine, 214(7), 1877-1888. https://doi.org/10.1084/jem.20161924

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.

In: Journal of Experimental Medicine, Vol. 214, No. 7, 01.07.2017, p. 1877-1888.

Research output: Contribution to journalArticle

Tsuda, T, Takefuji, M, Wettschureck, N, Kotani, K, Morimoto, R, Okumura, T, Kaur, H, Eguchi, S, Sakaguchi, T, Ishihama, S, Kikuchi, R, Unno, K, Matsushita, K, Ishikawa, S, Offermanns, S & Murohara, T 2017, 'Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction', Journal of Experimental Medicine, vol. 214, no. 7, pp. 1877-1888. https://doi.org/10.1084/jem.20161924
Tsuda T, Takefuji M, Wettschureck N, Kotani K, Morimoto R, Okumura T et al. Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction. Journal of Experimental Medicine. 2017 Jul 1;214(7):1877-1888. https://doi.org/10.1084/jem.20161924
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. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 7. pp. 1877-1888.
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