Research Achievements

May 30, 2017  PRESS RELEASE

Scientists identify protein linked to chronic heart failure

A Nagoya University-led research team has identified a receptor protein on the surface of heart cells that promotes chronic heart failure. 

press released on May 26, 2017 by Rockefeller University Press


Caption: A sustained increase in Ucn2 levels and Crhr2 activation causes a mouse heart to grow abnormally large (right), a response that impairs cardiac function and leads to heart failure. ©Tsuda et al., 2017


Researchers in Japan have identified a receptor protein on the surface of heart cells that promotes chronic heart failure. The study, "Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction," which will be published May 26 in The Journal of Experimental Medicine, suggests that inhibiting this protein could help treat a disease that affects more than 20 million people worldwide.


Chronic heart failure is caused by a variety of conditions that damage the heart, including coronary heart disease, hypertension, and diabetes. Although the heart initially tries to compensate for this damage and maintain its function by, for example, growing larger, cardiac function gradually declines until the heart is no longer able to pump enough blood and oxygen around the body. According to the CDC, about 5.7 million adults in the US have heart failure, and around half of these patients die within 5 years of their initial diagnosis. Indeed, heart failure contributes to as many as one in nine deaths across the country.


A team of researchers led by Mikito Takefuji from Nagoya University School of Medicine discovered that a signaling protein called corticotropin releasing hormone receptor 2 (Crhr2) is expressed on the surface of heart muscle cells, or cardiomyocytes, and that Crhr2 levels increase in mice suffering from heart failure.


Crhr2 is a G protein-coupled receptor whose ability to alter cardiomyocyte function is activated by a protein called urocortin 2 (Ucn2). Ucn2 levels were elevated in the blood of both mice and human patients with chronic heart failure, the researchers found. Sustained treatment of otherwise healthy mice with Ucn2 was sufficient to reduce cardiac function.


Takefuji and colleagues found that the activation of Crhr2 by Ucn2 stimulates several downstream signaling pathways that result in the expression of genes that impair heart function. Mice lacking Crhr2 were protected from the effects of Ucn2 and were resistant to developing heart failure. A small molecule that inhibits Crhr2 was similarly effective in maintaining cardiac function after damage to the heart.


G protein-coupled receptors such as Crhr2 are considered to be relatively easy to target with specific drugs. "Our results suggest that constitutive Crhr2 activation causes cardiac dysfunction and that Crhr2 blockade could be a promising therapeutic strategy for patients with chronic heart failure," Takefuji says.




The article, "Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction" was published in the Journal of Experimental Medicine at DOI: 10.1084/jem.20161924?PR




Authors:  Takuma Tsuda1, Mikito Takefuji1, Nina Wettschureck2, Kazuhiko Kotani3, Ryota Morimoto1, Takahiro Okumura1, Harmandeep Kaur2, Shunsuke Eguchi1, Teruhiro Sakaguchi1, Sohta Ishihama1, Ryosuke Kikuchi4, Kazumasa Unno1, Kunihiro Matsushita5, Shizukiyo Ishikawa3, Stefan Offermanns2, and Toyoaki Murohara1


1 Department of Cardiology, Nagoya University School of Medicine, Nagoya, Japan

2 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

3 Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan

4 Department of Medical Technique, Nagoya University Hospital, Nagoya, Japan

5 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA



Related Links:

More details (news release by Nagoya University Graduate School of Medicene) 


Department of Cardiology, Nagoya University Graduate School of Medicine



Media Coverage:


Healthline, "Scientists Looking Into the Causes of Chronic Heart Failure", by Tim Newman

MedicalExpress Newswise

ScienceNewsline, Medicine

Medical News Today

Today Topics

hindustan times



Critic Brain

The Medical News




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). 







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