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

• 批准号: 8282860
• 负责人: Richard T Clements
• 金额: $ 24.9万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282860
• 关键词: Acidosis; Binding; Binding Proteins; Biological Preservation; Blood; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiopulmonary Bypass; Catheters; 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; Induced Heart Arrest; Injury; Intervention; Ischemia; Literature; Location; Low Cardiac Output Syndrome; Mediating; Metabolic; Muscle Cells; Myocardial; Myocardial Stunning; Myocardium; Operative Surgical Procedures; Oxidants; Patients; Pattern; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Play; Prophylactic treatment; Proteins; Rattus; Research Design; Risk; Role; Signal Transduction; Solutions; Staining method; Stains; Testing; Therapeutic Intervention; Time; Tissues; Treatment Protocols; base; design; gene therapy; heart cell; improved; mortality; mutant; natural hypothermia; overexpression; repaired; response; treatment strategy

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 surgicallyinduced 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 nonphosphorylated 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 nonphosphorylated 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

大多数冠状动脉搭桥术（CABG）和瓣膜维修手术使用心脏杂草质和 心肺旁路（CP/CPB）分别阻止心脏并系统地循环氧气 血。低温性心脏杂志溶液在长时间外科手术诱导的过程中提供心肌保护 全球性缺血否则将被证明是致命的。但是，在心脏地统治期间逮捕了心脏的心脏 手术会导致可逆性缺血损伤，表现出可行心肌的收缩性受损 降低心脏功能（又称心肌惊人）。在大多数患者中，这个临时 损害很快解决，但是约有10％可以发展出相关的心脏低输出综合症 持续数小时到几天，大大增加了死亡率的风险。遵循CP/CPB，HSP27和Cryab是 在多个残基上磷酸化。文献中的当前数据表明，非磷酸化的存在 SHSP对缺血性收缩功能有益，并且缺血性侮辱（包括 CP/CPB）诱导Hsp27和Cryab的磷酸化，并随后耗尽非磷酸化 SHSP池，可能在心肌收缩缺陷或令人惊叹的情况下发挥作用。这些研究是 围绕中心假设设计，即保留非磷酸化的HSP27和Cryab水平 将减少或阻止CP引起的心肌收缩性缺陷。这些研究将在目标I中进行 - 确定CP/CPB诱导的Hsp27和Cryab磷酸化的上游信号传导机制。 AIM II-确定磷酸突变的SHSP的过表达是否会减少心脏双毛诱导的收缩性 孤立的心肌细胞缺陷。 AIM III-确定特定的心脏收缩信号传导机制 与缺血诱导的SHSP蛋白改变有关。实验干预措施（药理 和遗传方法）将使用孤立的大鼠心肌细胞和Langendorff灌注 心。 如果这些目标成功，这些研究将增强我们对CP诱导的收缩的理解 赤字，并提出可以大大改善当前心肌保护和的治疗策略 减少与心脏手术相关的并发症