TY - JOUR
T1 - Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction
AU - Tsuda, Takuma
AU - Takefuji, Mikito
AU - Wettschureck, Nina
AU - Kotani, Kazuhiko
AU - Morimoto, Ryota
AU - Okumura, Takahiro
AU - Kaur, Harmandeep
AU - Eguchi, Shunsuke
AU - Sakaguchi, Teruhiro
AU - Ishihama, Sohta
AU - Kikuchi, Ryosuke
AU - Unno, Kazumasa
AU - Matsushita, Kunihiro
AU - Ishikawa, Shizukiyo
AU - Offermanns, Stefan
AU - Murohara, Toyoaki
N1 - Funding Information:
We thank the staff from the Division of Experimental Animals, Nagoya University School of Medicine for assisting with animal experiments. This work was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to M. Takefuji) and by the Takeda Science Foundation (to M. Takefuji). The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Tsuda et al.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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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U2 - 10.1084/jem.20161924
DO - 10.1084/jem.20161924
M3 - Article
C2 - 28550160
AN - SCOPUS:85022035015
SN - 0022-1007
VL - 214
SP - 1877
EP - 1888
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -