Abstract
BackgroundCa2+/calmodulin-dependent protein kinase II (CaMKII)-dependent L-type calcium channel (LTCC) current (ICa) remodeling is an important contributor to the disruption of calcium homeostasis in heart failure (HF). We have reported that Kv4.3 proteins play an important role in delicate regulation of the membrane-associated CaMKII activity in ventricular myocytes. Here, we investigated the effect of in vivo Kv4.3 expression on ICa in HF left ventricular (LV) myocytes.ResultsKv4.3 expression reduced overall CaMKII autophosphorylation with much greater reduction in the membrane compartmentalized CaMKII activity. ICa density in subepicardial (SEP) and subendocardial (SEN) myocytes was proportionately reduced, without changing the transmural gradient. While the time course of ICa decay was hastened, the voltage-dependence of ICa activation and inactivation, however, remained unchanged. ICa recovery from inactivation was significantly accelerated. In line with the partial inhibition of CaMKII, the frequency-dependent Ca2+-induced ICa facilitation was recovered in the HF myocytes transfected with Kv4.3.Materials and MethodsPressure-overload HF was induced by thoracic aortic banding. Kv4.3 expression was achieved by Ad-Kv4.3 injection in the LV myocardium. ICa was recorded in dissociated SEP and SEN myocytes using whole-cell patch clamp method.ConclusionsKv4.3 expression in HF ventricle can effectively reverse ICa remodeling via inhibition of the membrane-associated CaMKII, pointing to Kv4.3 restoration as a potential therapeutic approach for the disordered calcium regulation in HF.
Highlights
ICa is the key mediator for the excitation-contraction (E-C) coupling in cardiomyocytes
Kv4.3 expression in heart failure (HF) ventricle can effectively reverse ICa remodeling via inhibition of the membrane-associated calmodulin-dependent protein kinase II (CaMKII), pointing to Kv4.3 restoration as a potential therapeutic approach for the disordered calcium regulation in HF
Kv4.3 transfection in HF ventricular myocytes to the left ventricular (LV) myocardium in the HF mice. 7 days after in vivo adenovirus injection, HF mice transfected with Ad-Kv4.3 (n = 10) was used for myocyte isolation
Summary
ICa is the key mediator for the excitation-contraction (E-C) coupling in cardiomyocytes. CaMKII plays a key role in regulation of E-C coupling by phosphorylation of a number of proteins involved in Ca2+ handling, such as LTCC, ryanodine receptor (RyR2), sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLB) [1]. It is a known powerful stimulator of the excitation-transcription (E-T) coupling mediated by class II histone deacetylases and myocyte enhancer factor 2 [2] and a arrhythmogenic molecule by www.impactjournals.com/oncotarget regulation of several important membrane ion channels [3], of which the ICa, transient outward current (Ito) and late sodium current (INaL) are most extensively studied [4, 5]. In line with the partial inhibition of CaMKII, the frequency-dependent Ca2+-induced ICa facilitation was recovered in the HF myocytes transfected with Kv4.3
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