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Tyrosine Kinase Fyn Is a Novel Regulator of NADPH Oxidase 4 in Cardiac Remodeling

      NADPH oxidase 4 (Nox4) is a major sources of reactive oxygen species (ROS) in the heart and plays a crucial role in the regulation of growth and death in cardiomyocytes. Cardiac hypertrophy and dysfunction in response to pressure overload (PO) were significantly attenuated in cardiac-specific Nox4 knockout (KO) mice, and those were accompanied by preservation of mitochondrial function. Recently, we elucidated the modulation of Nox4 through post-translational mechanisms. Yeast two-hybrid screening and in vitro binding assay demonstrated that Fyn, a Src family tyrosine kinase, directly interacted with Nox4. Nox4 and Fyn were co-localized in mitochondria in cardiomyocytes. Downregulation of Fyn enhanced Nox4-induced mitochondrial O2 production and apoptosis in cardiomyocytes. Fyn was activated by overexpression of Nox4. In vitro kinase assay and mass spectrometry analysis showed that Fyn directly phosphorylated tyrosine-566 of Nox4. Fyn KO mice showed exacerbated LV remodeling in response to PO compared with wild-type mice, accompanied by increases in O2 production in mitochondria and apoptosis in the heart. Deletion of Nox4 attenuated this LV remodeling in Fyn KO mice. Expression levels of Fyn and Nox4 phosphorylated at tyrosine-566 in human failing hearts were significantly decreased compared with control subjects. Fyn negatively regulates cell death as a sensor and regulator of Nox4-derived ROS in failing hearts. Fyn-Nox4 axis is a potential therapeutic target for heart failure.
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