title: 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.
authors.forename: Shouji
authors.initials: S
authors.lastname: Matsushima
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.forename: Narayani
authors.initials: N
authors.lastname: Nagarajan
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Oka
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D020257:Ventricular Remodeling
chemical_list: D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014443:Tyrosine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C498911:Nox4 protein, rat; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn