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.

摘要：心肌惊人存在以下与选举心脏骤停相关的缺血性侮辱在大多数心脏手术中，并显着促进了患者的发病率和死亡率。期间手术，心脏杂期溶液提供了重要的心脏保护作用。缺血性损伤。但是，在这些手术过程中，仍存在重大伤害。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通道（BKCA），如果驾驶激活会减轻与缺血性侮辱相关的心肌惊人在心脏手术期间，以及2）如果促进线粒体重组和功能的新策略是可行的治疗策略。线粒体K+介导的心脏保护的机制目前是未知。我们提供了初步数据，即活动BKCA通道的激活剂或过表达可改善LV 与分离的细胞和动物模型相关的缺血性损伤后的功能和血液动力学心脏病逮捕。我们还提供了新的证据，表明BKCA激活可以改善心脏保护通过改变线粒体结构蛋白并增加电子传输链的形成超复合物，从而提供更有效的细胞呼吸，并减少活性氧一代。当前的建议将研究线粒体K+介导的新机制心脏保护特定于K+依赖性的线粒体Cristae连接蛋白的调制复合物，线粒体超复合形成，改善呼吸和ROS减少。在此外，还努力翻译这些研究，并验证了相关发现 CP/CPB的临床前大动物模型以及人类心脏中提出的病理侮辱的定义心脏手术前后组织。这种机制的潜在阐明将对缺血性损伤和许多其他心肌代谢改变。该提议以三个具体目的：i）确定呼吸超复合物和CRISTAE重塑在BKCA介导的增强中的作用体外心肌保护。 BKCA介导的心脏保护的机制（呼吸，呼吸道将使用孤立的遗传和药理操作的心肌细胞。 ii）确定BKCA介导的超级复杂性是否造型增强心脏固定逮捕后心脏收缩功能和心脏保护再灌注后体内。小鼠孤立的心脏将受到缺血性心脏全新的逮捕和再灌注有和没有BKCA通道药物激活剂和遗传干预措施。 iii）确定是否相似在接受CP/CPB的人类使用心肌组织样本之前，存在病理机制然后绕过后，最后确定BKCA激活是否促进了超复合形式并减少在临床相关的CP/CPB大型动物模型中，心肌令人惊叹。