Journal
CIRCULATION RESEARCH
Volume 104, Issue 1, Pages 79-86Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.183475
Keywords
reactive oxidative species; early afterdepolarization; triggered activity; arrhythmia; CaM kinase
Funding
- NIH/National Heart, Lung, and Blood Institute [P50 HL53219, P01 HL078931]
- Laubisch and Kawata Endowments
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In the heart, oxidative stress caused by exogenous H2O2 has been shown to induce early afterdepolarizations (EADs) and triggered activity by impairing Na current (I-Na) inactivation. Because H2O2 activates Ca2+/calmodulin kinase (CaMK)II, which also impairs I-Na inactivation and promotes EADs, we hypothesized that CaMKII activation may be an important factor in EADs caused by oxidative stress. Using the patch-clamp and intracellular Ca (Ca-i) imaging in Fluo-4 AM-loaded rabbit ventricular myocytes, we found that exposure to H2O2 (0.2 to 1 mmol/L) for 5 to 15 minutes consistently induced EADs that were suppressed by the I-Na blocker tetrodotoxin (10 mu mol/L), as well as the I-Ca,I-L blocker nifedipine. H2O2 enhanced both peak and late I-Ca,I-L, consistent with CaMKII-mediated facilitation. By prolonging the action potential plateau and increasing Ca influx via I-Ca,I-L, H2O2-induced EADs were also frequently followed by DADs in response to spontaneous (ie, non-I-Ca,I-L-gated) sarcoplasmic reticulum Ca release after repolarization. The CaMKII inhibitor KN-93 (1 mu mol/L; n = 4), but not its inactive analog KN-92 (1 mu mol/L, n = 5), prevented H2O2-induced EADs and DADs, and the selective CaMKII peptide inhibitor AIP (autocamtide-2-related inhibitory peptide) (2 mu mol/L) significantly delayed their onset. In conclusion, H2O2-induced afterdepolarizations depend on both impaired I-Na inactivation to reduce repolarization reserve and enhancement of I-Ca,I-L to reverse repolarization, which are both facilitated by CaMKII activation. Our observations support a link between increased oxidative stress, CaMKII activation, and afterdepolarizations as triggers of lethal ventricular arrhythmias in diseased hearts. ( Circ Res. 2009; 104: 79-86.)
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