Published online before print November 26, 2008, doi: 10.1161/CIRCRESAHA.108.183475
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 17, 2008
Revised on November 18, 2008
Accepted on November 18, 2008
Oxidative Stress–Induced Afterdepolarizations and Calmodulin Kinase II Signaling
Lai-Hua Xie ;
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.
* To whom correspondence should be addressed. 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 TA by impairing Na current (INa) inactivation. Because H2O2 activates Ca2+/calmodulin kinase (CaMK)II, which also impairs INa 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 (Cai) 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 INa blocker tetrodotoxin (10 µmol/L), as well as the ICa,L blocker nifedipine. H2O2 enhanced both peak and late ICa,L, consistent with CaMKII-mediated facilitation. By prolonging the action potential plateau and increasing Ca influx via ICa,L, H2O2-induced EADs were also frequently followed by DADs in response to spontaneous (ie, non–ICa,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 INa inactivation to reduce repolarization reserve and enhancement of ICa,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
This article has been cited by other articles:
 |
|
 |
|
  N. Morita, A. A. Sovari, Y. Xie, M. C. Fishbein, W. J. Mandel, A. Garfinkel, S.-F. Lin, P.-S. Chen, L.-H. Xie, F. Chen, et al. Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1594 - H1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Belevych, D. Terentyev, S. Viatchenko-Karpinski, R. Terentyeva, A. Sridhar, Y. Nishijima, L. D. Wilson, A. J. Cardounel, K. R. Laurita, C. A. Carnes, et al. Redox modification of ryanodine receptors underlies calcium alternans in a canine model of sudden cardiac death Cardiovasc Res, August 14, 2009; (2009) cvp246v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, R. W. Joyner, M. B. Wagner, J. Cheng, D. Lai, and B. H. Crawford Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1227 - H1235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sato, L.-H. Xie, A. A. Sovari, D. X. Tran, N. Morita, F. Xie, H. Karagueuzian, A. Garfinkel, J. N. Weiss, and Z. Qu Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias PNAS, March 3, 2009; 106(9): 2983 - 2988. [Abstract] [Full Text] [PDF]
|
|