CaMKII in Sinus Node Physiology and Disease

描述（由申请人提供）：在最初的资助期间，我们的小组确定了多功能的Ca 2+和钙调蛋白依赖性蛋白激酶II（CaMKII）作为生理，“战斗或逃跑”，心率增加的必要信号。我们发现，CaMK II对心率的作用的细胞机制与增加肌浆网Ca 2+泄漏有关，但独立于If“起搏器”电流。我们还发现，过度的CaMKII激活导致窦房结（SAN）功能障碍（SND）的条件下，增加氧化应激，增加SAN细胞凋亡。SND引起症状性心动过缓和猝死，特别是在患有高血压或心力衰竭的患者和动物模型中，所述高血压或心力衰竭是以肾素-血管紧张素II（Ang II）信号传导轴的过度活化和活性氧物质（ROS）升高为标志的病症。总之，我们的研究表明，CaMKII对生理心率增加很重要，但过量的CaMKII活性会促进SND。CaMKII作为生理和病理信号的这种双重作用在心肌生理学中具有重要的相似性，其中CaMKII可以支持力-频率响应，并且在疾病中，过度氧化的CaMKII（ox-CaMKII）有助于心肌病和心律失常。我们解释了SAN中出现的证据，表明CaMKII抑制减慢心率，同时在高风险临床环境中防止由于SND导致的过度心动过缓，通过Ang II输注在小鼠中建模。我们的数据表明，CaMKII抑制剂最终可以作为一种单一的非手术疗法，用于调节心率和预防高危患者的SND。我们对这种竞争性更新应用的总体指导假设是，SAN线粒体的CaMKII调节增强了生理反馈，以使能量需求与ATP合成相匹配，并使战斗或飞行心率增加，但过度的CaMKII活性导致线粒体Ca 2+过载，从而促进SAN细胞死亡和SND。我们将使用以下具体目标来测试这种创新和新颖的机制假设：目的1-确定线粒体CaMKII在SAN细胞生理学和SND中的作用。目的2-测试IMCU在SAN功能和SND中的作用。目的3-确定MCU是否是CaMKII对SAN生理学和SND影响的关键靶标。

DESCRIPTION (provided by applicant): 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.