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
Department of Cardiology, Nagoya University School of Medicine, Nagoya, Japan.
Department of Cardiology, Nagoya University School of Medicine, Nagoya, Japan
J Exp Med. 2017 Jul 3;214(7):1877-1888. doi: 10.1084/jem.20161924. Epub 2017 May 26.
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.
当心脏无法有效地泵血并维持组织灌注时，就会发生心力衰竭。尽管在过去几十年中有众多治疗进展，但慢性心力衰竭患者的预后仍然很差，这凸显了识别其他病理生理因素的必要性。在此，我们表明促肾上腺皮质激素释放激素受体2（Crhr2）是一种在心肌细胞中高度表达的G蛋白偶联受体，持续输注Crhr2激动剂尿皮质素2（Ucn2）可降低小鼠的左心室射血分数。此外，与健康对照相比，心力衰竭患者的血浆Ucn2水平高出7.5倍。此外，心肌细胞特异性缺失Crhr2可保护小鼠免受压力超负荷诱导的心脏功能障碍。用Crhr2拮抗剂治疗的小鼠失去了适应性不良的3'-5'-环磷酸腺苷（cAMP）依赖性信号传导，并且在面对超负荷时不会发生心力衰竭。总体而言，我们的结果表明，Crhr2的组成性激活会导致心脏功能障碍，并表明Crhr2阻断是慢性心力衰竭患者一种有前景的治疗策略。
