Inhibition of the voltage-gated potassium channel Kv1.5 by hydrogen sulfide attenuates remodeling through S-nitrosylation-mediated signaling

The voltage-gated K⁺ channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K⁺ current (IKur) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H₂S) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5. Pacing induced remodeling resulted in shorting action potential duration, enhanced both Kv1.5 channel and H₂S producing enzymes protein expression in HL-1 cardiomyocytes. H₂S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H₂S also inhibited recombinant hKv1.5, lead to nitric oxide (NO) mediated S-nitrosylation and activated endothelial nitric oxide synthase (eNOS) by increased phosphorylation of Ser1177, prevention of NO formation precluded these effects. Regulation of Ikur by H₂S has important cardiovascular implications and represents a novel and potential therapeutic target.