Effect of the thioredoxin system in IGF‐1‐mediated de‐remodeling of cardiac K+ channels; role of ASK1‐JNK signaling

Abstract

c‐Jun NH2‐terminal kinase (JNK) plays a major role in the response of cells to oxidative stress. We found that JNK was activated in rat heart with chronic myocardial infarction (MI) compared with controls, as assessed by Western blotting and JNK assay. In voltage‐clamp studies of post‐MI ventricular myocytes down‐regulation of transient outward K+ current (Ito) was reversed by the JNK inhibitor SP600125 or peptide inhibitor JNKI‐1. We also examined apoptosis signal‐regulating kinase (ASK1), which activates JNK and which is normally inhibited by reduced thioredoxin (Trx). Using a co‐immunoprecipitation assay we found that ASK1‐Trx binding was decreased post‐MI, which is consistent with activation of ASK1‐JNK signaling. To further probe the impact of the Trx system on ASK1‐JNK signaling we studied the effects of IGF‐1 which regulates anti‐apoptotic and cell survival pathways. In voltage‐clamp studies IGF‐1 increased Ito density in myocytes from MI hearts and this effect was blocked by the thioredoxin reductase (TrxR) inhibitor auranofin. In isolated MI hearts perfused with IGF‐1, JNK activity was decreased and auranofin blocked this effect. IGF‐1 also increased TrxR and K+ channel protein expression in MI hearts. Our data suggest that K+ channel expression is regulated by the Trx system whose loss of function post‐MI underlies Ito remodeling via activation of ASK1‐JNK signaling.Supported by NIH grant HL066446.