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 1

ox-CaMKII is increased in heart failure patients and in Ang II–infused mice.

Options: View larger image (or click on image) Download as PowerPoint
ox-CaMKII is increased in heart failure patients and in Ang II–infused m...
(A) Representative immunoblots showing ox-CaMKII and total CaMKII from right atrial tissue obtained from heart failure patients with SND requiring pacemaker (HF+PM) implantation, heart failure patients without SND (HF–PM), and controls (–PM). The lanes were run on the same gel but were noncontiguous. (B) Summary data for ox-CaMKII and total CaMKII in HF+PM (n = 5), HF–PM (n = 6), and –PM (n = 10) patients (*P < 0.05, #P < 0.01). (C) Increased ox-CaMKII normalized to total CaMKII from patient samples shown in B (*P < 0.05 and #P < 0.01). (D) Representative immunoblots showing ox-CaMKII and total CaMKII from right atrial tissue obtained from WT mice infused with Ang II or saline for 3 weeks. The lanes were run on the same gel but were noncontiguous. (E) Summary data for ox-CaMKII and total CaMKII in Ang II– (n = 6) and saline-infused (n = 6) mice (*P = 0.03). (F) Increased ox-CaMKII normalized to total CaMKII in mouse samples shown in E (*P = 0.02). (G) Representative immunofluorescence images showing that 3 weeks of Ang II infusion increases SAN ox-CaMKII. SAN area is identified by HCN4 immunostaining (green). Scale bars: 50 μm. (H) Summary data showing increased ox-CaMKII normalized to total CaMKII in SAN tissue from mice treated with 3 weeks of Ang II or saline infusion (n = 4/group, *P < 0.01).