Abstract
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.
Highlights
The heart is capable of remodeling in response to workload by modulating protein synthesis and degradation
We found that P2Y2 receptor (P2Y2R) contributes to adenosine 5′-triphosphate (ATP)-induced reactive oxygen species (ROS) production and atrophy
Atrophy of cardiomyocyte and extracellular release of ATP were observed in nutritional deficiency, which were dependent on TRPC3 and NADPH oxidase (Nox)[2] (Figs 6 and 7)
Summary
The heart is capable of remodeling in response to workload by modulating protein synthesis and degradation. In multiple types of muscle atrophy, protein synthesis is attenuated with the upregulation of ubiquitin ligases atrogin-1/MAFbx and muscle ring finger-1 (MuRF1), and several autophagy markers including LC3-phosphatidylethanolamine conjugate (LC3-II), cathepsin L and beclin[5,6] These cellular responses are mediated by FoxO family of transcription factors, such as FoxO1 and FoxO35,6. Despite being a potent activator of Ca2+-dependent nuclear factor of activated T cells (NFAT), ATP does not induce cardiomyocyte hypertrophy[16,17] This could be partially explained by our previous study, where ATP activates endothelial nitric oxide synthase which negatively regulates NFAT-dependent hypertrophic responses in cardiomyocytes[18]. It remains to be elucidated whether and how ATP induces cardiomyocyte atrophy
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