Role of γ‐glutamyl transpeptidase in redox regulation of K+ channel remodeling in heart failure

Abstract

γ‐Glutamyl transpeptidase (γGT) regulates cellular GSH levels in response to extracellular GSH (GSHo). The objective of this study was to identify the role of γGT in reversing K+ channel remodeling in heart failure, which was induced in rats by chronic myocardial infarction (MI). Assays of tissue extracts from MI hearts showed marked increases in γGT activity, protein and mRNA in left ventricle and septum compared with sham hearts. Voltage‐clamp studies of ventricular myocytes from MI hearts showed that down‐regulation of transient outward K+ current (Ito) was reversed after 4‐5 h by 10 mM GSHo or N‐acetylcysteine (NACo). The effect of GSHo but not NACo was blocked by γGT inhibitors acivicin or S‐hexyl‐GSH. Inhibition of GSH synthesis by buthionine sulfoximine did not prevent up‐regulation of Ito by GSHo, but an SOD mimetic (MnTPyP) and catalase blocked recovery of Ito by GSHo. Confocal microscopy using the fluorogenic dye DCFH showed that GSHo increased ROS generation by MI myocytes and to a lesser extent in sham myocytes. Moreover, up‐regulation of Ito by GSHo was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, AG1024) or thioredoxin reductase (auranofin, 13‐cis‐retinoic acid). These data suggest that GSHo elicits γGT‐ and ROS‐dependent transactivation of tyrosine kinase signaling which up‐regulates K+ channel activity/expression via redox mechanisms.Supported by NIH grant HL066446.