Abstract
Pathologic electrical remodeling and attenuated cardiac contractility are featured characteristics of heart failure. Coinciding with these remodeling events is a loss of the K+ channel interacting protein, KChIP2. While, KChIP2 enhances the expression and stability of the Kv4 family of potassium channels, leading to a more pronounced transient outward K+ current, Ito,f, the guinea pig myocardium is unique in that Kv4 expression is absent, while KChIP2 expression is preserved, suggesting alternative consequences to KChIP2 loss. Therefore, KChIP2 was acutely silenced in isolated guinea pig myocytes, which led to significant reductions in the Ca2+ transient amplitude and prolongation of the transient duration. This change was reinforced by a decline in sarcomeric shortening. Notably, these results were unexpected when considering previous observations showing enhanced ICa,L and prolonged action potential duration following KChIP2 loss, suggesting a disruption of fundamental Ca2+ handling proteins. Evaluation of SERCA2a, phospholamban, RyR, and sodium calcium exchanger identified no change in protein expression. However, assessment of Ca2+ spark activity showed reduced spark frequency and prolonged Ca2+ decay following KChIP2 loss, suggesting an altered state of RyR activity. These changes were associated with a delocalization of the ryanodine receptor activator, presenilin, away from sarcomeric banding to more diffuse distribution, suggesting that RyR open probability are a target of KChIP2 loss mediated by a dissociation of presenilin. Typically, prolonged action potential duration and enhanced Ca2+ entry would augment cardiac contractility, but here we see KChIP2 fundamentally disrupts Ca2+ release events and compromises myocyte contraction. This novel role targeting presenilin localization and RyR activity reveals a significance for KChIP2 loss that reflects adverse remodeling observed in cardiac disease settings.
Highlights
The development of heart failure, whether from atrial fibrillation, hypertrophy, or myocardial infarction, culminates in compromised contractility and the insufficient ability to pump blood for the demands of the body
We previously showed that acute loss of KChIP2 in guinea pig myocytes led to prolonged action potential duration (APD) through increased L-type Ca2+ current (ICa,L) density [8]
Given that we previously showed acute silencing of KChIP2 in guinea pig myocytes led to enhanced ICa,L and APD prolongation [8], paired with the consistent KChIP2 loss observed in cardiac pathologies, we wanted to evaluate what influence acute silencing of KChIP2 has on Ca2+ handling and contractility
Summary
The development of heart failure, whether from atrial fibrillation, hypertrophy, or myocardial infarction, culminates in compromised contractility and the insufficient ability to pump blood for the demands of the body. The potassium channel interacting protein 2 (KChIP2) is a protein that consistently experiences degradation and sustained loss early in hypertrophy and heart failure [1, 2]. This reproducibility suggests its loss may not just be symptomatic, but relevant to the progression and ailments of heart failure. KChIP2 is well-established as an accessory subunit and modulator of the Kv4 family of potassium channels, responsible for encoding the fast transient outward potassium current, Ito,f, critical for early phase 1 repolarization during the cardiac action potential [3]. This loss in Ito,f does not appear to be a precipitating event in heart failure, as animal models with the Kv4 gene removed and resulting APD prolongation, do not display signs of heart failure remodeling [6]
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