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Rationale: The fast transient outward K+ current (I to,f ) plays a critical role in early repolarization of the heart.I to,f is consistently downregulated in cardiac disease. Despite its importance, the regulation ofI to,f in disease remains poorly understood.Objective: Because the transcription factor nuclear factor (NF)-κB is activated in cardiac hypertrophy and disease, we studied the role of NF-κB in mediatingI to,f reductions induced by hypertrophy.Methods and Results: Culturing neonatal rat ventricular myocytes in the presence of phenylephrine (PE) plus propranolol (Pro), to selectively activate α1 -adrenergic receptors, caused reductions inI to,f , as well as KChIP2 and Kv4.3 expression, while increasing Kv4.2 expression. Inhibition of NF-κB, via overexpression of a phosphorylation-deficient mutant of IκBα (IκBαSA) prevented PE/Pro-induced reductions inI to,f and KChIP2 mRNA, without affecting Kv4.2 or Kv4.3 expression, suggesting NF-κB mediates theI to,f reductions by repressing KChIP2. Indeed, overexpression of the NF-κB activator IκB kinase-β also decreased KChIP2 expression andI to,f (despite increasing Kv4.2), whereas IκBαSA overexpression elevated KChIP2 and decreased Kv4.2 levels. In addition, the classic NF-κB activator tumor necrosis factor α also induced NF-κB–dependent reductions of KChIP2 andI to,f . Finally, inhibition of calcineurin did not prevent PE/Pro-induced reductions in KChIP2.Conclusions: NF-κB regulates KChIP2 and Kv4.2 expression. The reductions inI to,f observed following α-adrenergic receptor stimulation or tumor necrosis factor α application require NF-κB–dependent decreases in KChIP2 expression.

Nuclear Factor κB Downregulates the Transient Outward Potassium Current I to,f Through Control of KChIP2 Expression

Nuclear Factor κB Downregulates the Transient Outward Potassium Current I _to,f Through Control of KChIP2 Expression