TY - JOUR
T1 - Loss of K+ currents in heart failure is accentuated in KChIP2 deficient mice
AU - Grubb, Søren Jahn
AU - Speerschneider, Tobias
AU - Occhipinti, Dona
AU - Fiset, Céline
AU - Olesen, Søren-Peter
AU - Thomsen, Morten Bækgaard
AU - Callø, Kirstine
N1 - This article is protected by copyright. All rights reserved.
PY - 2014/8
Y1 - 2014/8
N2 - The Role of KChIP2 in Heart Failure Introduction KV4 together with KV Channel-Interacting Protein 2 (KChIP2) mediate the fast recovering transient outward potassium current (Ito,f) in the heart. KChIP2 is downregulated in human heart failure (HF), potentially underlying the loss of Ito,f. We investigated remodeling associated with HF hypothesizing that KChIP2 plays a central role in the modulation of outward K+ currents in HF. Methods and Results HF was induced by aortic banding in wild-type (WT) and KChIP2 deficient (KChIP2-/-) mice, evaluated by echocardiography. Action potentials were measured by floating microelectrodes in intact hearts. Ventricular cardiomyocytes were isolated and whole-cell currents were recorded by patch clamp. Left ventricular action potentials in KChIP2-/- mice were prolonged in a rate dependent manner, consistent with patch-clamp data showing loss of a fast recovering outward K+ current and upregulation of the slow recovering I to,s and IKur. HF decreased all outward K+ currents in WT mice and did not change the relative contribution of I to,f in WT mice. Compared to WT HF, KChIP2-/- HF had a larger reduction of K+-current density. However, the relative APD prolongation caused by HF was shorter for KChIP2-/- compared with WT, and the APs of the 2 HF mouse types were indistinguishable. Conclusion I to,f is just one of many K+ currents being downregulated in murine HF. The downregulation of repolarizing currents in HF is accentuated in KChIP2-/- mice. However, the prolongation of APs associated with HF is less in KChIP2-/- compared to WT, suggesting other compensatory mechanism(s) in the KChIP2-/- mouse.
AB - The Role of KChIP2 in Heart Failure Introduction KV4 together with KV Channel-Interacting Protein 2 (KChIP2) mediate the fast recovering transient outward potassium current (Ito,f) in the heart. KChIP2 is downregulated in human heart failure (HF), potentially underlying the loss of Ito,f. We investigated remodeling associated with HF hypothesizing that KChIP2 plays a central role in the modulation of outward K+ currents in HF. Methods and Results HF was induced by aortic banding in wild-type (WT) and KChIP2 deficient (KChIP2-/-) mice, evaluated by echocardiography. Action potentials were measured by floating microelectrodes in intact hearts. Ventricular cardiomyocytes were isolated and whole-cell currents were recorded by patch clamp. Left ventricular action potentials in KChIP2-/- mice were prolonged in a rate dependent manner, consistent with patch-clamp data showing loss of a fast recovering outward K+ current and upregulation of the slow recovering I to,s and IKur. HF decreased all outward K+ currents in WT mice and did not change the relative contribution of I to,f in WT mice. Compared to WT HF, KChIP2-/- HF had a larger reduction of K+-current density. However, the relative APD prolongation caused by HF was shorter for KChIP2-/- compared with WT, and the APs of the 2 HF mouse types were indistinguishable. Conclusion I to,f is just one of many K+ currents being downregulated in murine HF. The downregulation of repolarizing currents in HF is accentuated in KChIP2-/- mice. However, the prolongation of APs associated with HF is less in KChIP2-/- compared to WT, suggesting other compensatory mechanism(s) in the KChIP2-/- mouse.
U2 - 10.1111/jce.12422
DO - 10.1111/jce.12422
M3 - Journal article
C2 - 24678923
SN - 1045-3873
VL - 25
SP - 896
EP - 904
JO - Journal of Cardiovascular Electrophysiology
JF - Journal of Cardiovascular Electrophysiology
IS - 8
ER -