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Surgical Cardioprotection Through BKCa-Dependent Modulation of Mitochondrial Supercomplexes

通过 BKCa 依赖性线粒体超级复合物调节进行外科心脏保护

基本信息

批准号：
10207742
负责人：
Richard T Clements
金额：
$ 37.31万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207742
关键词：
Animal Model Applications Grants Architecture Automobile Driving Blood flow Bypass COX7A2L gene Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiac health Cardiopulmonary Bypass Cell Respiration Cell model Cells Coronary Circulation Crista ampullaris Data Disease Effectiveness Electron Transport Family suidae Generations Genetic Grant Harvest Heart Heart Arrest Hour Human Human Rights In Vitro Individual Induced Heart Arrest Infarction Injury Inner mitochondrial membrane Investigation Ischemia Knockout Mice Laboratories Mediating Membrane Metabolic Mitochondria Mitochondrial Matrix Modeling Modification Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Contraction Myocardial Infarction Myocardial Stunning Myocardial tissue Myocardium OPA1 gene Operative Surgical Procedures Pathologic Patients Pharmacology Potassium Channel Procedures Production Proteins Publications Reactive Oxygen Species Recovery Recovery of Function Reperfusion Therapy Reporting Research Respiration Role Signal Transduction Structural Protein Structure Superoxides Testing Therapeutic Tissue Sample Tissues Translations Type 2 diabetic Vasospasm auricular appendage cardioprotection clinically relevant gene therapy heart function hemodynamics hypercholesterolemia improved ischemic injury knock-down mortality mouse model non-diabetic novel novel strategies overexpression pre-clinical prohibitin protein complex repaired respiratory response vasoconstriction voltage

项目摘要

Abstract: Myocardial stunning is present following ischemic insults associated with elective cardiac arrest during the majority of cardiac surgeries and significantly contributes to patient morbidity and mortality. During surgery, cardioplegia solutions provide significant cardioprotection from what would otherwise be lethal ischemic injury. However, there is still significant injury during these procedures to the myocardial tissue. This grant seeks to determine 1) the mechanism of cardioprotection associated with activation of a mitochondrial K+ channel (BKCa) and if driving activation will mitigate myocardial stunning associated with ischemic insults during cardiac surgery, and 2) if novel strategies to promote mitochondrial reorganization and function are viable therapeutic strategies. The mechanism of mitochondrial K+-mediated cardioprotection is currently unknown. We present preliminary data, that activators or overexpression of active BKCa channels improves LV function and hemodynamics following ischemic injury associated with isolated cell and animal models of cardioplegic arrest. We also present novel evidence that BKCa activation may improve cardioprotection through alterations in mitochondrial structural proteins and increase the formation of electron transport chain supercomplexes, thereby providing more efficient cellular respiration, and decreased reactive oxygen species generation. The current proposal will investigate the novel mechanism of mitochondrial K+ mediated cardioprotection with specific focus on K+-dependent modulation of mitochondrial cristae junction protein complexes, enhanced mitochondrial supercomplex formation, improved respiration, and decreased ROS. In addition, there is a strong effort towards translation of these studies, with verification of the relevant findings in a pre-clinical large animal model of CP/CPB and definition of the proposed pathological insult in human heart tissue before and after cardiac surgery. The potential elucidation of this mechanism will have implication for ischemic injury and numerous other myocardial metabolic alterations. The proposal is in three specific aims: I) Determine the role of respiratory supercomplexes and cristae remodeling in BKCa-mediated enhanced myocardial protection in vitro. The mechanism of BKCa-mediated cardioprotection (respiration, respiratory supercomplex formation, ATP generation, superoxide production, etc...) will be evaluated using isolated myocytes with genetic and pharmacologic manipulation. II) Determine if BKCa-mediated supercomplex formation enhances cardiac contractile function and cardioprotection following cardioplegic arrest and reperfusion ex vivo. Mouse isolated hearts will be subjected to ischemic cardioplegic arrest and reperfusion with and without BKCa channel pharmacologic activators and genetic interventions. III) Determine if similar pathological mechanisms are present in humans undergoing CP/CPB using myocardial tissue samples before and after bypass, and finally, determine if BKCa activation promotes supercomplex formaton and reduces myocardial stunning in a clinically relevant diseased large animal model of CP/CPB.

翻译后摘要：心肌顿抑是目前以下缺血性损伤与选择性心脏骤停在大多数心脏手术期间，并显著导致患者发病率和死亡率。期间手术，心脏停搏液提供了显着的心脏保护，否则将是致命的缺血性损伤然而，这些手术过程中仍然对心肌组织造成严重损伤。这格兰特试图确定1）与线粒体K+激活相关的心脏保护机制，如果驱动激活将减轻与缺血性损伤相关的心肌顿抑，在心脏手术期间，以及2）如果促进线粒体重组和功能的新策略，可行的治疗策略。线粒体K+介导的心脏保护机制目前是未知我们目前的初步数据表明，激活剂或活性BKCa通道的过度表达可以改善LV 功能和血流动力学后缺血性损伤与分离的细胞和动物模型，心脏停搏我们还提出了新的证据表明，BKCa激活可能会改善心脏保护通过改变线粒体结构蛋白和增加电子传递链的形成超复合物，从而提供更有效的细胞呼吸，并减少活性氧一代目前的建议将探讨线粒体K+介导的新机制，线粒体嵴连接蛋白K+依赖性调节的心脏保护作用复合物，增强线粒体超复合物的形成，改善呼吸作用，降低ROS。在此外，还大力翻译这些研究报告，并在 CP/CPB的临床前大型动物模型和人类心脏中拟议病理损伤的定义心脏手术前后的组织这一机制的潜在阐明将对以下方面产生影响：缺血性损伤和许多其他心肌代谢改变。该提案有三个具体目标：确定呼吸超复合物和嵴重塑在BKCa介导的增强的体外心肌保护作用。BKCa介导的心脏保护机制（呼吸，呼吸超复合物形成、ATP生成、超氧化物生成等）将使用隔离的通过遗传和药理学操作。II）确定BKCa介导的超复合物是否形成增强心脏收缩功能和心脏停搏后的心脏保护，离体再灌注。将小鼠离体心脏进行缺血性心脏停搏和再灌注有和没有BKCa通道药理学激活剂和遗传干预。3.确定是否相似病理机制存在于使用心肌组织样本进行CP/CPB的人中，旁路后，最后确定BKCa激活是否促进超复合物形成并减少在CP/CPB的临床相关患病大型动物模型中的心肌顿抑。