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 6

SAN and atrial fibrosis are promoted by Ang II and contribute to SND.

Options: View larger image (or click on image) Download as PowerPoint
SAN and atrial fibrosis are promoted by Ang II and contribute to SND. (A...
(A) Representative samples of Masson’s trichrome staining showing increased SAN fibrosis in mice infused with Ang II compared with saline for 3 weeks. Scale bars: 100 μm. (B) Summary data showing increased fibrosis in the SAN (intranodal, P = 0.06, n = 3/group) and in SAN-adjacent tissue (perinodal, *P = 0.03, n = 3/group). (C) Top row: Representative atrial isolate and conduction velocity measurement. Bottom row: Representative pseudocolored isochrones from optical mapping show decreased conduction velocity (CV) in WT mice infused with Ang II for 3 weeks (lower right panel) compared with WT mice infused with saline for 3 weeks (lower left panel). AVJ, atrioventricular junction; AVN, atrioventricular node; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; RAA, right atrial appendage; SVC, superior vena cava. White asterisks denote the earliest activation in the SAN. (D) Summary data for CV measured from Langendorff-perfused hearts isolated from mice infused with Ang II or saline for 3 weeks. CV was measured in the RA (n = 5/group, P = 0.07 baseline and *P = 0.03 Iso) and LA (#P = 0.001 baseline and †P = 0.001 Iso, n = 5/group). The P values represent comparisons between Ang II– and saline-infused mice.