Nuclear Factor κB Downregulates the Transient Outward Potassium Current Ito,f Through Control of KChIP2 Expression
Rationale: The fast transient outward K+ current (Ito,f) plays a critical role in early repolarization of the heart. Ito,f is consistently downregulated in cardiac disease. Despite its importance, the regulation of Ito,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 mediating Ito,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 in Ito,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 in Ito,f and KChIP2 mRNA, without affecting Kv4.2 or Kv4.3 expression, suggesting NF-κB mediates the Ito,f reductions by repressing KChIP2. Indeed, overexpression of the NF-κB activator IκB kinase-β also decreased KChIP2 expression and Ito,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 and Ito,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 in Ito,f observed following α-adrenergic receptor stimulation or tumor necrosis factor α application require NF-κB–dependent decreases in KChIP2 expression.
- Received July 26, 2010.
- Revision received January 1, 2011.
- Accepted January 7, 2011.
- © 2011 American Heart Association, Inc.