ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism.
ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism.
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DOI：
10.1038/ncomms13016
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发表时间：
2016-09-28
影响因子：
16.6
通讯作者：
Oike, Yuichi
中科院分区：
文献类型：
--
作者：
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
在高血压等情况下，随着工作负荷的增加，会出现一种心脏保护反应，这种反应会改变心室收缩能力或促进心肌细胞扩大。当这种反应过度时，就会发生病理性的心脏重构，这可能会发展为心力衰竭，这是全球范围内的主要死亡原因。这种反应背后的机制还没有完全被理解。在此，我们报道了血管生成素样蛋白2(ANGPTL2)在病理重塑的小鼠和人类心脏中的表达增加，而在耐力训练诱导的生理性心脏重塑中心脏ANGPTL2的表达降低。在心脏中过表达ANGPTL2的小鼠表现出由于AKT和SERCA(SERCA)2a信号失活和心肌能量代谢降低而导致的心功能障碍。相反，Angptl2基因敲除小鼠表现出左心室收缩能力增强，AKT-SERCA2a信号和能量代谢上调。最后，在压力超负荷的小鼠中，ANGPTL2基因敲除可以改善心功能不全。总体而言，这些研究表明，治疗性抑制ANGPTL2可以对抗心力衰竭的发展。心脏对增加的工作负荷的反应是扩大心肌细胞以保持功能，但在病理学上肥大会导致心力衰竭。在这里，作者表明，心脏中的ANGPTL2活性通过对AKT-SERCA2a信号和心肌能量的影响，对于确定良性肥厚与病理性肥厚至关重要。
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 Ca2+-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. Heart responds to increased workload by enlarging cardiomyocytes to preserve function, but in pathologies hypertrophy leads to heart failure. Here the authors show that ANGPTL2 activity in the heart is critical for determining beneficial vs. pathological hypertrophy via its effect on AKT-SERCA2a signaling and myocardial energy.
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影响因子：
49.6
作者：
Bui, Anh L.;Horwich, Tamara B.;Fonarow, Gregg C.
通讯作者：
Fonarow, Gregg C.
DOI：
10.1016/j.bbrc.2004.08.083
发表时间：
2004-10-08
影响因子：
3.1
作者：
Kamon, J;Yamauchi, T;Kadowaki, T
通讯作者：
Kadowaki, T
DOI：
10.1016/j.bbrc.2003.09.154
发表时间：
2003-10-31
影响因子：
3.1
作者：
Guo, DF;Chenier, I;Inagami, T
通讯作者：
Inagami, T
影响因子：
37.8
作者：
Gielen, Stephan;Schuler, Gerhard;Adams, Volker
通讯作者：
Adams, Volker
影响因子：
20.1
作者：
Dai DF;Johnson SC;Villarin JJ;Chin MT;Nieves-Cintrón M;Chen T;Marcinek DJ;Dorn GW 2nd;Kang YJ;Prolla TA;Santana LF;Rabinovitch PS
通讯作者：
Rabinovitch PS