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: 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
• 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

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体外循环（CP/CPB）来分别停止心脏并使含氧血液进行全身循环。低温心脏停跳液可在长时间手术引起的整体缺血期间提供心肌保护，否则将致命。然而，手术期间心脏停搏会导致可逆性缺血性损伤，表现为存活心肌收缩力受损和心脏功能下降（又称心肌顿抑）。在大多数患者中，这种暂时性损伤很快就会消失，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，从而大大增加死亡风险。 CP/CPB 后，HSP27 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 HSP27 和cryAB 磷酸化的缺血性损伤（包括 CP/CPB）以及随后非磷酸化 sHSP 池的耗尽，可能在心肌收缩缺陷或致晕中发挥作用。这些研究围绕一个中心假设而设计，即保持非磷酸化 HSP27 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 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。目标 II - 确定磷酸突变体 sHSP 的过度表达是否会减少离体心肌细胞中心脏停搏液诱导的收缩缺陷。目标 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，并提出可以极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