Kv4.3 expression reverses I(Ca) remodeling in ventricular myocytes of heart failure

BACKGROUND: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent L-type calcium channel (LTCC) current (I(Ca)) 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 I(Ca) in HF left ventricular (LV) myocytes. RESULTS: Kv4.3 expression reduced overall CaMKII autophosphorylation with much greater reduction in the membrane compartmentalized CaMKII activity. I(Ca) density in subepicardial (SEP) and subendocardial (SEN) myocytes was proportionately reduced, without changing the transmural gradient. While the time course of I(Ca) decay was hastened, the voltage-dependence of I(Ca) activation and inactivation, however, remained unchanged. I(Ca) recovery from inactivation was significantly accelerated. In line with the partial inhibition of CaMKII, the frequency-dependent Ca(2+)-induced I(Ca) facilitation was recovered in the HF myocytes transfected with Kv4.3. MATERIALS AND METHODS: Pressure-overload HF was induced by thoracic aortic banding. Kv4.3 expression was achieved by Ad-Kv4.3 injection in the LV myocardium. I(Ca) was recorded in dissociated SEP and SEN myocytes using whole-cell patch clamp method. CONCLUSIONS: Kv4.3 expression in HF ventricle can effectively reverse I(Ca) 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.