Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

Shouji Matsushima, Junya Kuroda, Peiyong Zhai, Tong Liu, Shohei Ikeda, Narayani Nagarajan, Shin Ichi Oka, Takashi Yokota, Shintaro Kinugawa, Chiao Po Hsu, Hong Li, Hiroyuki Tsutsui, Junichi Sadoshima

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29 Citations (Scopus)

Abstract

NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O2 - production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling.

Original languageEnglish
Pages (from-to)3403-3416
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Matsushima, S., Kuroda, J., Zhai, P., Liu, T., Ikeda, S., Nagarajan, N., Oka, S. I., Yokota, T., Kinugawa, S., Hsu, C. P., Li, H., Tsutsui, H., & Sadoshima, J. (2016). Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. Journal of Clinical Investigation, 126(9), 3403-3416. https://doi.org/10.1172/JCI85624