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: 7514228
• 负责人: Richard T Clements
• 金额: $ 9.72万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 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/7514228
• 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; Protein Overexpression; 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; day; design; gene therapy; improved; mortality; mutant; natural hypothermia; programs; repaired; response

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）： 大多数冠状动脉旁路移植术（CABG）和瓣膜修复手术使用心脏停搏液和心肺转流术（CP/CPB）来分别使心脏停搏和全身循环含氧血液。低温心脏停搏液在长时间手术引起的全脑缺血期间提供心肌保护，否则会被证明是致命的。然而，手术期间心脏停搏导致可逆性缺血性损伤，表现为存活心肌的收缩力受损和心脏功能降低（也称为心肌顿抑）。在大多数患者中，这种暂时性损害很快就会消退，但约10%的患者可能会出现持续数小时至数天的相关心脏低输出量综合征，这大大增加了死亡风险。在CP/CPB之后，HSP 27和cryAB在多个残基上被磷酸化。目前文献中的数据表明，非磷酸化sHSP的存在有利于缺血后收缩功能，并且诱导HSP 27和cryAB磷酸化的缺血性损伤（包括CP/CPB）以及随后的非磷酸化sHSP池的消耗可能在心肌收缩缺陷或顿抑中起作用。这些研究是围绕中心假设设计的，即保留非磷酸化HSP 27和cryAB水平将减少或阻止CP诱导的心肌收缩力缺陷。这些研究将在目标I -确定CP/CPB诱导的HSP 27和cryAB磷酸化的上游信号传导机制中进行。目的II -确定磷酸化突变的sHSP的过表达是否会减少心脏停搏诱导的离体心肌细胞收缩缺陷。目的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（药理学和遗传学方法）。 如果这些目标是成功的，这些研究将提高我们对CP诱导的收缩缺陷的理解，并提出治疗策略，可以大大改善目前的心肌保护和减少心脏手术相关的并发症