NMRK2-YAP-NADK axis preserves redox protection against myocardial ischemia/reperfusion injury.

Abstract

Substantial oxidative stress during myocardial ischemia/reperfusion (I/R) injury precipitates cell death and heart failure, for which translatable redox therapies remain scarce. Here, we show that nicotinamide riboside kinase 2 (NMRK2) is rapidly upregulated after reperfusion and exerts redox protection by a previously unrecognized mechanism. We established myocardial I/R injury in mice and hypoxia/reoxygenation (H/R) injury in cardiomyocytes. By elevating NADPH, restoring NAD/NADH, increasing GSH/GSSG and activating Trx1, NMRK2 overexpression enhanced cellular antioxidant capacity and reduced oxidative damage during both myocardial I/R and cellular H/R injury. Knockdown of NAD kinase (NADK) abolished these protective effects. Mechanistically, nucleocytoplasmic fractionation and immunofluorescence confirmed robust Yes-associated protein (YAP) nuclear entry in NMRK2-overexpressing cells; Co-IP revealed NMRK2-induced disruption of the integrin β-YAP interaction; knockdown of integrin β reduced NADK expression and increased YAP phosphorylation at Ser127; and ChIP-qPCR and luciferase assays demonstrated that YAP directly binds the NADK promoter (-1500 to -1000 bp) for its transcriptional activation. In conclusion, NMRK2 sustains redox protection by disrupting the integrin β-YAP complex and driving YAP-dependent NADK transcription, providing a readily translatable therapy against myocardial I/R injury.