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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling.

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.

SUBMITTER: Matsushima S

PROVIDER: S-EPMC5004961 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling.

Matsushima Shouji S Kuroda Junya J Zhai Peiyong P Liu Tong T Ikeda Shohei S Nagarajan Narayani N Oka Shin-Ichi S Yokota Takashi T Kinugawa Shintaro S Hsu Chiao-Po CP Li Hong H Tsutsui Hiroyuki H Sadoshima Junichi J

The Journal of clinical investigation 20160815 9

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-induc ...[more]

PMID: 27525436

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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling.

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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling.

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