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 O 2 -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.

Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4

“…However, the time course that we have observed for the insulin-dependent H 2 O 2 response is not compatible with genetic induction of NOX4, and indicates that activation of NOX4 likely occurs at the post-translational level. The study of post-translational modifications of NOX4 remains a nascent field with limited biochemical tools available and only one phosphorylation site (Tyr 566 ) having being recently described as modifying enzyme activity (44). Another important question prompted by these studies is the mechanism by which NOX4 attenuates beta adrenergic signaling.…”

Hydrogen (H2) Inhibits Isoproterenol-Induced Cardiac Hypertrophy via Antioxidative Pathways

“…ROS produced by NADPH oxidase has the ability to stimulate and amplify mitochondrial ROS generation and induce mitochondrial dysfunction (Zorov et al, 2000; Dai et al, 2011a). Therefore, tyrosine kinase FYN interacts with the C-terminal domain of NOX4, and phosphorylates the tyrosine 566 on NOX4, thereby inhibiting apoptosis in the heart and preventing cardiac remodeling after pressure overload (Matsushima et al, 2016). Overexpression of catalase targeted to mitochondria, but not the overexpression of wild-type peroxisomal catalase, protects against ANG II-induced cardiac hypertrophy, fibrosis and mitochondrial damage, as well as heart failure induced by overexpression of Gαq (Dai et al, 2011b).…”

Responses to reductive stress in the cardiovascular system

“…Nox4 is unique in that it only requires p22phox for its activity, and is considered to be constitutively active. Recent findings, however, suggest that Nox4 activity may be negatively regulated post-translationally via phosphorylation by a Src family tyrosine kinase, FYN [38]. Other Nox, such as Nox1 and Nox2, are regulated by various post-transcriptional mechanisms, including phosphorylation of regulatory subunits.…”

“…Regardless of the knockout results, a similar MHC-driven cardiac-specific promoter was used to overexpress Nox4 in in the study reporting a protective mechanism as well as the study reporting that Nox4 augments cardiac dysfunction. One possible explanation is that the time-course for cardiac dysfunction may differ in these models [38], allowing for compensatory, protective actions that are Nox4-dependent in the suprarenal banding model, or there may be other mechanistic differences between these pressure-overload models that account for the distinct outcomes. Alternatively, the level of Nox4 overexpression may differ in the context of these transgenic lines established by different investigators.…”

“…Nox4 modulation by FYN, a Src family tyrosine kinase, suggests the existence of additional ROS-mediated feedback mechanisms that may play a role in cardiac stress responses [38]. FYN was shown specifically to mitigate Nox4-mediated ROS production by phosphorylating tyrosine 566 on Nox4.…”