Small heat shock proteins in surgically-induced myocardial stunning

手术引起的心肌顿抑中的小热休克蛋白

基本信息

批准号：
8054663
负责人：
Richard T Clements
金额：
$ 9.72万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-23 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8054663
关键词：
Acidosis Animals Award Biological Preservation Blood Bypass Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiopulmonary Bypass Catheters Conflict (Psychology)Coronary Artery Bypass Crystallins Data Disease Drug Delivery Systems Gene Delivery Genetic Heart Heart Arrest Heat Shock Protein 27 Heat shock proteins Hour Hypoxia Impairment In Vitro Individual Induced Heart Arrest Injury Instruction Intervention Investigation Ischemia Literature Location Low Cardiac Output Syndrome Lung Mediating Mentors Metabolic Muscle Cells Myocardial Myocardial Stunning Myocardium Operative Surgical Procedures Oxidants Patients Pattern Phase Phosphorylation Phosphorylation Inhibition Phosphotransferases Play Positioning Attribute Principal Investigator Prophylactic treatment Proteins Rattus Research Design Research Personnel Rights Risk Role Signal Transduction Solutions Staining method Stains Techniques Testing Therapeutic Intervention Time TimeLine Tissues Treatment Protocols base clinically relevant design gene therapy improved mortality mutant natural hypothermia overexpression programs repaired response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The majority of coronary artery bypass grafting (CABG) and valve repair surgeries use cardioplegia and cardiopulmonary bypass (CP/CPB) to respectively arrest the heart and systemically circulate oxygenated blood. Hypothermic cardioplegia solutions provide myocardial protection during prolonged surgically- induced global ischemia that would otherwise prove lethal. However, cardioplegic arrest of the heart during surgery results in reversible ischemic injury that manifests in impaired contractility of viable myocardium and reductions in cardiac function (a.k.a myocardial stunning). In the majority of patients, this temporary impairment resolves quickly, however ~ 10 % can develop an associated cardiac low output syndrome lasting hours to days that greatly enhances the risk of mortality. Following CP/CPB, HSP27 and cryAB are phosphorylated on multiple residues. Current data in the literature suggests that the presence of non-phosphorylated sHSP is beneficial for post ischemic contractile function, and that ischemic insults (including CP/CPB) that induce phosphorylation of HSP27 and cryAB, and subsequent depletion of the non-phosphorylated sHSP pool, may play a role in myocardial contractile deficits or stunning. These studies are designed around the central hypothesis that preservation of non-phosphorylated HSP27 and cryAB levels will reduce or block CP-induced deficits in myocardial contractility. These studies will be performed in Aim I - Determine the upstream signaling mechanism of CP/CPB-induced HSP27 and cryAB phosphorylation. Aim II - Determine if overexpression of phospho-mutant sHSP's will reduce cardioplegia-induced contractile deficits in isolated myocytes. Aim III - Determine specific cardiac contractile signaling mechanisms associated with ischemia-induced alterations in sHSP proteins. Experimental interventions (pharmacological and genetic approaches) will be performed using isolated rat cardiomyocytes and Langendorff perfused hearts. If these Aims are successful, these studies will enhance our understanding of CP-induced contractile deficits, and suggest treatment strategies that could greatly improve current myocardial protection and reduce complications associated with cardiac surgery

描述（由申请人提供）：大多数冠状动脉搭桥术（CABG）和瓣膜修复手术都使用心骨和心肺旁路（CP/CPB）分别阻止心脏并系统地循环氧气的血液。在长期通过手术诱发的全球缺血期间，低温心脏杂志溶液提供了心肌保护，否则该缺血将被证明是致命的。然而，手术过程中心脏的心脏按平停滞导致可逆性缺血性损伤表现出可行心肌的收缩性受损和心脏功能减少的收缩力（又称心肌惊人）。在大多数患者中，这种暂时的损害很快就可以解决，但是约有10％可以发展出持续数小时至几天的相关心脏低输出综合症，从而大大增加了死亡率的风险。在CP/CPB之后，HSP27和CryAb在多个残基上被磷酸化。文献中的当前数据表明，非磷酸化的SHSP的存在对缺血后的收缩功能有益，并且缺血性损伤（包括CP/CPB）诱导Hsp27和CryAb的磷酸化，以及随后的非磷酸化SHSP池的耗尽，可能会在肌无力中扮演肌无力的缺陷。这些研究是围绕中心假设设计的，即保存非磷酸化的HSP27和CryAB水平将减少或阻止CP诱导的心肌收缩性缺陷。这些研究将在目标I-确定CP/CPB诱导的Hsp27和Cryab磷酸化的上游信号传导机制中进行。 AIM II-确定磷酸突变体SHSP的过表达是否会减少心脏外皮诱导的分离肌细胞中的收缩缺损。 AIM III-确定与缺血诱导的SHSP蛋白改变相关的特定心脏收缩信号传导机制。将使用分离的大鼠心肌细胞和Langendorff灌注心脏进行实验干预措施（药理和遗传方法）。如果这些目标成功，这些研究将增强我们对CP引起的收缩缺陷的理解，并提出可以大大改善当前心肌保护并减少与心脏手术相关的并发症的治疗策略