TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy
TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy
复制标题
DOI：
10.1038/s41598-019-46252-2
复制
发表时间：
2019-07
影响因子：
4.6
通讯作者：
Suhaini Sudi;Tomohiro Tanaka;Sayaka Oda;K. Nishiyama;Akiyuki Nishimura;Caroline Sunggip;S. Mangmool;Takuro Numaga‐Tomita;M. Nishida
中科院分区：
文献类型：
--
作者：
Suhaini Sudi;Tomohiro Tanaka;Sayaka Oda;K. Nishiyama;Akiyuki Nishimura;Caroline Sunggip;S. Mangmool;Takuro Numaga‐Tomita;M. Nishida
心肌萎缩是由严重的营养不良和/或机械负荷引起的，其特征是心肌细胞的大小和收缩能力降低。细胞外三磷酸腺苷(ATP)被认为是一种危险信号，对细胞体积具有负性调节作用。然而，细胞外三磷酸腺苷是否导致心肌细胞萎缩尚不清楚。在这里，我们报道了ATP通过P2Y2受体诱导新生大鼠心肌细胞(NRCM)萎缩而没有细胞死亡。由于NOX2和典型的瞬时受体电位3(TRPC3)之间的物理相互作用增加，ATP通过增加NADPH氧化酶(NOx)2蛋白的数量而导致活性氧物种(ROS)的过量产生。这种由ATP介导的TRPC3-NOX2复合体的形成也参与了营养缺乏引起的NRCM萎缩的病理生理过程。值得注意的是，TRPC3或NOX2的敲除抑制了营养缺乏诱导的ATP释放，以及ROS的产生和NRCM的萎缩。综上所述，我们认为，由细胞外ATP激活的TRPC3-NOX2轴是介导营养缺乏所致心肌细胞萎缩的关键成分。
Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5′-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.