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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

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Title: Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling
Authors: Matsushima, Shouji Browse this author →KAKEN DB
Kuroda, Junya Browse this author →KAKEN DB
Zhai, Peiyong Browse this author
Liu, Tong Browse this author
Ikeda, Shohei Browse this author
Nagarajan, Narayani Browse this author
Oka, Shin-ichi Browse this author
Yokota, Takashi Browse this author →KAKEN DB
Kinugawa, Shintaro Browse this author →KAKEN DB
Hsu, Chiao-Po Browse this author
Li, Hong Browse this author
Tsutsui, Hiroyuki Browse this author →KAKEN DB
Sadoshima, Junichi Browse this author
Issue Date: 2016
Publisher: American Society for Clinical Investigation
Journal Title: Journal of Clinical Investigation
Volume: 126
Issue: 9
Start Page: 3403
End Page: 3416
Publisher DOI: 10.1172/JCI85624
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.
Type: article
URI: http://hdl.handle.net/2115/76936
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 横田 卓

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