Angiotensin II infusion increased oxidized CaMKII and sinoatrial node cell apoptosis, leading to sinus node dysfunction, which was prevented by targeted CaMKII inhibition.
Does oxidized CaMKII cause sinus node dysfunction in mice?
Oxidized CaMKII is a key determinant of sinus node dysfunction, suggesting targeted CaMKII inhibition may prevent SND in high-risk patients.
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.
Swaminathan et al. (Mon,) conducted a other in Sinus node dysfunction. Angiotensin II infusion and CaMKII inhibition vs. Saline infusion was evaluated on Sinus node dysfunction (resting heart rate, sinus pauses, and sinoatrial node cell apoptosis). Angiotensin II infusion increased oxidized CaMKII and sinoatrial node cell apoptosis, leading to sinus node dysfunction, which was prevented by targeted CaMKII inhibition.