CaMKII in Sinus Node Physiology and Disease

描述(由申请人提供)：在最初的资助期间，我们的团队确定多功能钙和钙调蛋白依赖的蛋白激酶II(CaMKII)是生理性的、‘战斗或逃跑’，心率增加的必要信号。我们发现CaMKII对心率作用的细胞机制与增加肌浆网钙渗漏有关，但与IF‘起搏器’电流无关。我们还发现，在氧化应激增加的条件下，CaMKII的过度激活通过增加窦房结细胞的凋亡而导致窦房结功能障碍(SND)。SND导致症状性心动过缓和猝死，特别是在高血压或心力衰竭的患者和动物模型中，以肾素-血管紧张素II(Ang II)信号轴过度激活和活性氧(ROS)升高为标志。综上所述，我们的研究表明，CaMKII对生理性心率增加很重要，但过度的CaMKII活性会促进SND。CaMKII作为生理和病理信号的双重作用在心肌生理学和疾病中有重要的相似之处，在心肌生理学中，CaMKII可能支持力-频率反应，在疾病中，过量的氧化CaMKII(ox-CaMKII)可导致心肌病和心律失常。我们解读了SAN中的紧急证据，表明抑制CaMKII可以减缓心率，同时防止在高危临床环境中因SND而过度心动过缓，这是通过注射Ang II在小鼠身上建立的模型。我们的数据表明，在高危患者中，CaMKII抑制最终可能成为调节心率和预防SND的单一非手术疗法。我们对这一竞争性更新应用的总体指导假设是，CaMKII对SAN线粒体的调控增强了生理反馈，使能量需求与ATP合成相匹配，并使战斗或逃跑的心率增加，但过高的CaMKII活性会导致线粒体钙超载，从而促进SAN细胞死亡和SND。我们将使用以下具体目标来检验这一创新和新颖的机制假说：目的1-确定线粒体CaMKII在窦房结细胞生理学和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生理和SND影响的关键靶点。

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.