Small heat shock proteins in surgically-induced myocardial stunning

描述(由申请人提供)： 大多数冠状动脉搭桥术(CABG)和瓣膜修复术(CPB)分别使用心脏停搏液和体外循环(CP/CPB)来停止心脏跳动和使氧合血液系统循环。低温停搏液在手术诱导的长时间全球缺血期间提供心肌保护，否则将被证明是致命的。然而，术中心脏停搏会导致可逆的缺血性损伤，表现为存活心肌的收缩能力受损和心功能下降(也称为心肌顿抑)。在大多数患者中，这种暂时的损害很快就会消失，但约10%的患者会发展为相关的心脏低输出综合征，持续数小时至数天，从而极大地增加死亡的风险。在CP/CPB之后，HSP27和CryAB在多个残基上被磷酸化。目前的文献数据表明，非磷酸化SHSP的存在有利于缺血后的收缩功能，而诱导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，可能在心肌收缩功能障碍或顿抑中发挥作用。这些研究是围绕一个中心假设设计的，即保留非磷酸化的HSP27和CryAB水平将减少或阻断CP诱导的心肌收缩功能缺陷。这些研究旨在确定CP/CPB诱导的HSP27和CryAB磷酸化的上游信号机制。目的II-确定过表达磷酸化突变体SHSP是否能减少停搏液诱导的心肌细胞收缩功能障碍。目的III-确定与缺血诱导的SHSP蛋白改变相关的特定的心脏收缩信号机制。实验干预(药理学和遗传学方法)将使用分离的大鼠心肌细胞和朗宁多夫灌流的心脏进行。 如果这些目标成功，这些研究将加深我们对CP引起的收缩缺陷的理解，并提出治疗策略，可以极大地改善目前的心肌保护，减少与心脏手术相关的并发症

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