title: Oxidative-stress-induced afterdepolarizations and calmodulin kinase II signaling.
abstract: In the heart, oxidative stress caused by exogenous H(2)O(2) has been shown to induce early afterdepolarizations (EADs) and triggered activity by impairing Na current (I(Na)) inactivation. Because H(2)O(2) activates Ca(2+)/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 H(2)O(2) (0.2 to 1 mmol/L) for 5 to 15 minutes consistently induced EADs that were suppressed by the I(Na) blocker tetrodotoxin (10 micromol/L), as well as the I(Ca,L) blocker nifedipine. H(2)O(2) 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), H(2)O(2)-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 micromol/L; n=4), but not its inactive analog KN-92 (1 micromol/L, n=5), prevented H(2)O(2)-induced EADs and DADs, and the selective CaMKII peptide inhibitor AIP (autocamtide-2-related inhibitory peptide) (2 micromol/L) significantly delayed their onset. In conclusion, H(2)O(2)-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.
authors.affiliation: Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry, New Jersey-New Jersey Medical School, Newark, USA.
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Fuhua
authors.initials: F
authors.lastname: Chen
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D003064:Cnidarian Venoms / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003064:Cnidarian Venoms; D010455:Peptides; D026941:Sodium Channel Blockers; C514527:autocamptide-2-related inhibitory peptide II; D013779:Tetrodotoxin; C028800:toxin II (Anemonia sulcata); D006861:Hydrogen Peroxide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009543:Nifedipine; D002118:Calcium