During the initial funding period, our group identified the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) as a necessary signal for physiological, 'fight or flight', increases in heart rate. We showed that the cellular mechanisms for CaMKII actions on heart rate were related to increasing sarcoplasmic reticulum Ca2+ leak but independent of the If 'pacemaker'current. We also found that excessive CaMKII activation contributed to sinoatrial nodal (SAN) dysfunction (SND) under conditions of increased oxidative stress, by increasing SAN cell apoptosis. SND causes symptomatic bradycardia and sudden death, particularly in patients and animal models with hypertension or heart failure, conditions marked by hyper-activation of the renin-angiotensin II (Ang II) signaling axis and elevated reactive oxygen species (ROS). Taken together, our studies show that CaMKII is important for physiological heart rate increases, but excessive CaMKII activity promotes SND. This dual role of CaMKII as a physiological and pathological signal has important parallels in myocardial physiology, where CaMKII may support the force-frequency response, and in disease, where excessive oxidized CaMKII (ox-CaMKII) contributes to cardiomyopathy and arrhythmias. We interpret emergent evidence in SAN to suggest that CaMKII inhibition slows heart rate, while protecting against excessive bradycardia due to SND in high risk clinical settings, modeled in mice by Ang II infusion. Our data suggest that CaMKII inhibition could eventually serve as a single, non-surgical therapy for regulating heart rate and preventing SND in high-risk patients. Our overall guiding hypothesis for this competitive renewal application is that CaMKII regulation of SAN mitochondria enhances physiological feedback to match energy demand with ATP synthesis and enable fight or flight heart rate increases, but excessive CaMKII activity results in mitochondrial Ca2+ overload that promotes SAN cell death and SND. We will test this innovative and novel mechanistic hypothesis using the following specific aims:
Aim 1 - Determine the role of mitochondrial CaMKII in SAN cell physiology and SND.
Aim 2 - Test the role of IMCU in SAN function and SND.
Aim 3 - Establish whether the MCU is a critical target for CaMKII effects on SAN physiology and SND.
Sinoatrial nodal (SAN) cardiac pacemaker failure is a significant cause of morbidity and mortality in the United States. We spend over 2 billion dollars on permanent, surgically-implanted pacemakers annually. Pacemakers are a successful but highly imperfect therapy that do not treat the underlying disease and are subject to mechanical failure, infection and require repetitive surgical replacement. Thus, improved, non-invasive therapies for SAN failure would produce important public health benefits for Americans. Our proposal focuses on the role of CaMKII as a central, but neglected, signal for inducing SAN disease.
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|Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865|
|Takanari, Hiroki; Bourgonje, Vincent J A; Fontes, Magda S C et al. (2016) Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent. Cardiovasc Res 111:410-21|
|Wu, Yuejin; Valdivia, Héctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180|
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