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(Circulation Research. 2009;104:79.)
© 2009 American Heart Association, Inc.

Cellular Biology

Oxidative Stress–Induced Afterdepolarizations and Calmodulin Kinase II Signaling

Lai-Hua Xie, Fuhua Chen, Hrayr S. Karagueuzian, James N. Weiss

From the Department of Cell Biology and Molecular Medicine (L.-H.X.), University of Medicine and Dentistry, New Jersey–New Jersey Medical School, Newark; and Cardiovascular Research Laboratory (F.C., H.X.K., J.N.W.), David Geffen School of Medicine, University of California, Los Angeles.

Correspondence to James N. Weiss, MD, Division of Cardiology, Rm 3645 MRL Building, UCLA School of Medicine, Los Angeles, CA 90095. E-mail jweiss{at}mednet.ucla.edu

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 µmol/L), as well as the I_Ca,L blocker nifedipine. H₂O₂ enhanced both peak and late I_Ca,L, consistent with CaMKII-mediated facilitation. By prolonging the action potential plateau and increasing Ca influx via I_Ca,L, H₂O₂-induced EADs were also frequently followed by DADs in response to spontaneous (ie, non–I_Ca,L-gated) sarcoplasmic reticulum Ca release after repolarization. The CaMKII inhibitor KN-93 (1 µmol/L; n=4), but not its inactive analog KN-92 (1 µmol/L, n=5), prevented H₂O₂-induced EADs and DADs, and the selective CaMKII peptide inhibitor AIP (autocamtide-2–related inhibitory peptide) (2 µmol/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,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.

Key Words: reactive oxidative species • early afterdepolarization • triggered activity • arrhythmia • CaM kinase

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