| First Author | Wagner S | Year | 2011 |
| Journal | Circ Res | Volume | 108 |
| Issue | 5 | Pages | 555-65 |
| PubMed ID | 21252154 | Mgi Jnum | J:183493 |
| Mgi Id | MGI:5318818 | Doi | 10.1161/CIRCRESAHA.110.221911 |
| Citation | Wagner S, et al. (2011) Reactive oxygen species-activated Ca/calmodulin kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res 108(5):555-65 |
| abstractText | 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 CaMKIIdelta 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 mumol/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 mumol/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 CaMKIIdelta(-/-) 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 CaMKIIdelta(-/-) myocytes (versus WT). CaMKIIdelta(-/-) 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 CaMKIIdelta in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 mumol/L KN93 or 0.1 mumol/L AIP [autocamtide 2-related inhibitory peptide]). CONCLUSIONS: Free [Ca](i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIdelta 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. |
