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.