Oxidized CaMKII causes cardiac sinus node dysfunction in mice

Paari Dominic Swaminathan, Anil Purohit, Siddarth Soni, Niels Voigt, Madhu V. Singh, Alexey V. Glukhov, Zhan Gao, B. Julie He, Elizabeth D. Luczak, Mei Ling A. Joiner, William Kutschke, Jinying Yang, J. Kevin Donahue, Robert M. Weiss, Isabella M. Grumbach, Masahiro Ogawa, Peng Sheng Chen, Igor Efimov, Dobromir Dobrev, Peter J. MohlerThomas J. Hund, Mark E. Anderson

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47- - mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII - triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.

Original languageEnglish (US)
Pages (from-to)3277-3288
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number8
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Swaminathan, P. D., Purohit, A., Soni, S., Voigt, N., Singh, M. V., Glukhov, A. V., Gao, Z., He, B. J., Luczak, E. D., Joiner, M. L. A., Kutschke, W., Yang, J., Donahue, J. K., Weiss, R. M., Grumbach, I. M., Ogawa, M., Chen, P. S., Efimov, I., Dobrev, D., ... Anderson, M. E. (2011). Oxidized CaMKII causes cardiac sinus node dysfunction in mice. Journal of Clinical Investigation, 121(8), 3277-3288. https://doi.org/10.1172/JCI57833