Tian Zhe, Miyata Keishi, Kadomatsu Tsuyoshi, Horiguchi Haruki, Fukushima Hiroyuki, Tohyama Shugo, Ujihara Yoshihiro, Okumura Takahiro, Yamaguchi Satoshi, Zhao Jiabin, Endo Motoyoshi, Morinaga Jun, Sato Michio, Sugizaki Taichi, Zhu Shunshun, Terada Kazutoyo, Sakaguchi Hisashi, Komohara Yoshihiro, Takeya Motohiro, Takeda Naoki, Araki Kimi, Manabe Ichiro, Fukuda Keiichi, Otsu Kinya, Wada Jun, Murohara Toyoaki, Mohri Satoshi, Yamashita Jun K, Sano Motoaki, Oike Yuichi
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Nat Commun. 2016 Sep 28;7:13016. doi: 10.1038/ncomms13016.
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.
在诸如高血压等情况下，随着工作量增加会出现一种改变心室收缩力或促进心肌细胞增大的心脏保护反应。当这种反应过度时，就会发生病理性心脏重塑，进而可能发展为心力衰竭，这是全球主要的死亡原因。这种反应背后的机制尚未完全了解。在这里，我们报告血管生成素样蛋白2（ANGPTL2）在小鼠和人类病理性重塑心脏中的表达增加，而在小鼠耐力训练诱导的生理性心脏重塑中，心脏ANGPTL2表达降低。心脏中过表达ANGPTL2的小鼠表现出心脏功能障碍，这是由AKT失活和肌浆网Ca-ATP酶（SERCA）2a信号传导以及心肌能量代谢降低所致。相反，Angptl2基因敲除小鼠表现出左心室收缩力增加以及AKT-SERCA2a信号传导和能量代谢上调。最后，在承受压力过载的小鼠中敲低ANGPTL2可改善心脏功能障碍。总体而言，这些研究表明，治疗性抑制ANGPTL2可能对抗心力衰竭的发展。
