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 (I(Kur)) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H(2)S) 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 H(2)S producing enzymes protein expression in HL-1 cardiomyocytes. H(2)S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H(2)S 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 I(kur) by H(2)S has important cardiovascular implications and represents a novel and potential therapeutic target.