ROS-activated CaMKIIδ enhances late INa, leading to cellular Na and Ca overload, a process requiring free intracellular Ca and a functional sarcoplasmic reticulum.
ROS-activated CaMKIIδ enhances late INa, leading to cellular Na and Ca overload, which requires free intracellular Ca and a functional SR and may contribute to arrhythmias in heart failure.
RATIONALE: In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I(Na) leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation. OBJECTIVE: We tested whether CaMKIIδ is required for ROS-dependent late I(Na) regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. METHODS AND RESULTS: 40 μmol/L H(2)O(2) significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free Ca(i) (5 mmol/L BAPTA/1 mmol/L Br(2)-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 μmol/L), the H(2)O(2)-dependent CaMKII oxidation and autophosphorylation was abolished. H(2)O(2) significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H(2)O(2) increased late I(Na) (whole cell patch-clamp). This increase was abolished in CaMKIIδ(-/-) myocytes. H(2)O(2)-induced Na(i) and Ca(i) accumulation (SBFI sodium-binding benzofuran isophthalate and Indo-1 epifluorescence) was significantly slowed in CaMKIIδ(-/-) myocytes (versus WT). CaMKIIδ(-/-) myocytes developed significantly less H(2)O(2)-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I(Na), Na(i) and Ca(i) accumulation) were obtained by overexpression of CaMKIIδ in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 μmol/L KN93 or 0.1 μmol/L AIP autocamtide 2-related inhibitory peptide). CONCLUSIONS: Free Ca(i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIδ enhances late I(Na), which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression.
Wagner et al. (2011) studied Heart failure (cellular Na and Ca overload). H2O2 (Reactive Oxygen Species) and CaMKIIδ modulation vs. Wild-type or CaMKII inhibition was evaluated on CaMKII oxidation, autophosphorylation, and late INa augmentation. ROS-activated CaMKIIδ enhances late INa, leading to cellular Na and Ca overload, a process requiring free intracellular Ca and a functional sarcoplasmic reticulum.