CaMKII in Sinus Node Physiology and Disease

CaMKII 在窦房结生理学和疾病中的作用

基本信息

批准号：
8915241
负责人：
MARK E ANDERSON
金额：
$ 38.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-09 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915241
关键词：
ATP Synthesis Pathway Abbreviations American Angiotensin II Animal Model Apoptosis Arrhythmia Artificial cardiac pacemaker Boxing Bradycardia Cardiomyopathies Cell Death Cell physiology Cells Cessation of life Clinical Data Disease Disease Pathway Dominant-Negative Mutation Failure Feedback Figs - dietary Frequencies Functional disorder Funding Genetic Health Health Benefit Heart Heart Rate Heart failure Hypertension Implant Infection Infusion procedures Mechanics Mediating Mitochondria Modeling Morbidity - disease rate Mus Muscle Cells Myocardial Nature Nodal Operative Surgical Procedures Oxidative Stress Pacemakers Pathway interactions Patients Phosphorylation Physiological Physiology Play Public Health Reactive Oxygen Species Reagent Regulation Renin Reporting Role Sarcoplasmic Reticulum Signal Transduction Sinus Stress Sudden Death Testing Text Therapeutic Time Transgenic Organisms United States calmodulin-dependent protein kinase II fighting genetic approach high risk improved in vivo innovation mitochondrial dysfunction mitochondrial permeability transition pore mortality mouse model neglect novel prevent response

项目摘要

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.

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 Ca2+ 和钙调蛋白依赖性蛋白激酶 II (CaMKII) 是生理上“战斗或逃跑”心率增加的必要信号。我们表明，CaMKII 对心率的作用的细胞机制与增加肌浆网 Ca2+ 泄漏有关，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，过度的 CaMKII 激活会增加 SAN 细胞凋亡，从而导致窦房结 (SAN) 功能障碍 (SND)。 SND 会导致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，这些疾病的特征是肾素-血管紧张素 II (Ang II) 信号轴过度激活和活性氧 (ROS) 升高。综上所述，我们的研究表明 CaMKII 对于生理心率增加很重要，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中具有重要的相似之处，在心肌生理学中，CaMKII 可能支持力-频率响应，在疾病中，过度氧化的 CaMKII (ox-CaMKII) 会导致心肌病和心律失常。我们对 SAN 中的新证据进行了解释，表明 CaMKII 抑制可减慢心率，同时在高风险临床环境中防止因 SND 引起的过度心动过缓，通过 Ang II 输注在小鼠中建模。我们的数据表明，CaMKII 抑制最终可以作为一种单一的非手术疗法来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，CaMKII 对 SAN 线粒体的调节增强了生理反馈，使能量需求与 ATP 合成相匹配，并使战斗或逃跑心率增加，但过度的 CaMKII 活性会导致线粒体 Ca2+ 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一创新和新颖的机制假设：目标 1-确定线粒体 CaMKII 在 SAN 细胞生理学和 SND 中的作用。目标 2 - 测试 IMCU 在 SAN 功能和 SND 中的作用。目标 3 - 确定 MCU 是否是 CaMKII 对 SAN 生理学和 SND 影响的关键目标。