Oxidized CaMKII causes cardiac sinus node dysfunction in mice
Paari Dominic Swaminathan, … , Thomas J. Hund, Mark E. Anderson
Paari Dominic Swaminathan, … , Thomas J. Hund, Mark E. Anderson
Published July 25, 2011
Citation Information: J Clin Invest. 2011;121(8):3277-3288. https://doi.org/10.1172/JCI57833.
View: Text | PDF
Research Article

Oxidized CaMKII causes cardiac sinus node dysfunction in mice

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.

Authors

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. Mohler, Thomas J. Hund, Mark E. Anderson

×

Figure 3

Myocardial and SAN-targeted CaMKII inhibition protects against SND.

Options: View larger image (or click on image) Download as PowerPoint
Myocardial and SAN-targeted CaMKII inhibition protects against SND. (A) ...
(A) ECG-telemetered, unrestrained, and unanesthetized AC3-I transgenic mice (n = 8–10/group) infused with Ang II for 3 weeks have no significant decrease in resting HR or (B) reduction in ARHR or (C) increased bradycardia events. *P < 0.01 compared with baseline; †P < 0.01 compared with all other groups. (D) Ex vivo Langendorff-perfused AC3-I hearts isolated after 3 weeks of Ang II infusion have no significant increase in sinus pauses (n = 8/group). (E) Gene painting with an adenovirus-poloxamer mixture (see Methods) allowed for SAN-targeted expression of IRES eGFP from the CaMKIIN adenovirus (scale bars: 25 μm). (F) WT mice (n = 5–6/group) with SAN expression of CaMKIIN and eGFP were significantly (*P = 0.02) resistant to reduced resting HR after 3 weeks of Ang II infusion compared with WT mice with SAN eGFP expression alone. (G) Langendorff-perfused hearts from WT mice with SAN-targeted expression of CaMKIIN and eGFP were significantly (*P = 0.049, n = 5–6/group) protected against Ang II–induced increases in sinus pauses compared with WT mice expressing eGFP alone. (H) SAN-targeted CaMKIIN expression significantly protected against Ang II infusion induced CSNRT prolongation in response to 80-ms (*P = 0.04) and 100-ms (#P = 0.049) pacing cycle intervals. The same hearts were studied in G and H.