Roles of cardiac potassium channels in sepsis-induced cardiac dysfunction

Abstract

A cardiac potassium channel, the I_Ks channels composed of the alpha subunit KCNQ1 and beta subunit KCNE1, contributes to the repolarization phase of the cardiac action potential. Mutations in these genes are associated with the development of lethal arrhythmias due to congenital QT prolongation syndrome and are influenced by sympathetic nerve stimulation and sex hormones. As a molecular mechanism, we have demonstrated the involvement of a molecular complex of the KCNQ1 channel in the I_Ks regulation by intracellular Ca²⁺, cAMP , and NO. Our proteomic analysis revealed that the KCNQ1 molecular complex involves in Ca²⁺ signaling, epithelial junction signaling, mitochondrial dysfunction and so on, but the pathophysiological role has not been elucidated. Therefore, we aimed to test whether I_Ks channels activated by pathological Ca²⁺ overload may compensate for arrhythmias using genetically engineered (I_Ks-Tg) mice expressing cardiac human I_Ks channels. We employed a sepsis model (Cecal Slurry) intraperitoneal injection method) for pathological Ca²⁺ overload condition. We found that the sepsis score I_Ks-Tg male mice was significantly lower than that in wild-type mice. In this talk, I would like to discuss the molecular mechanisms of sepsis-induced cardiac dysfunction development based on patch clamp data of isolated cardiomyocytes.