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 P2Y2 receptors. 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.
　

Our current study uncovers a new pathway in the development of cardiomyocyte atrophy, where extracellular ATP, acting as a “danger signal”, mediates the interaction between TRPC3 channel protein and NADPH oxidase (Nox) 2 protein. This TRPC3-Nox2 complex contributes to nutritional deficiency-induced atrophy through increased ROS production by escaping Nox2 from ER-associated degradation.
 

 

Collaborative Researcher

Suhaini Sudi (Universiti Malaysia Sabah)
Caroline Sunggip (Universiti Malaysia Sabah)
Supachoke Mangmool (Mahidol University)
Takuro Numaga-Tomita (Shinshu University)

Funding

This research was funded by grants from JSPS KAKENHI No. 16H05092, 16KT0013, and 19H03383 (to M.N.), No. 19K16363 (to T. Tanaka), No. 17K15585 (to T. N-T.), No. 18K14921 (to K.N.) and Scientific Research on Innovative Areas (Research in a Proposed Research Area No. 18H04993 ‘Living in Space’ to T. N-T.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and The Uehara Memorial Foundation, Suzuken Memorial Foundation, The Naito Foundation and Takeda Science Foundation (to M.N.). This work was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research BINDS from AMED (JP19am0101091). This work was also supported by Cooperative Study Program of National Institute for Physiological Sciences and Spectrography and Bioimaging Facility, NIBB Core Research Facilities.