Small heat shock proteins in surgically-induced myocardial stunning

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)分别停止心脏跳动和全身氧合循环 血。低温停搏液在手术诱导的长时间心肌保护中的作用 全球缺血，否则将被证明是致命的。然而，在心脏停搏的过程中 手术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 心功能减退(亦称心肌顿抑)。在大多数患者中，这是暂时的 损害很快消失，但约10%可发展为相关的心脏低输出量综合征 持续数小时到数天，极大地增加了死亡风险。在CP/CPB之后，HSP27和CryAB是 多个残基上的磷酸化。目前文献中的数据表明，非磷酸化的存在 SHSP有益于缺血后收缩功能，而缺血损伤(包括 Cp/CPB)，诱导HSP27和CryAB的磷酸化，并随后耗尽非磷酸化的 SHSP池，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，即保持非磷酸化的HSP27和CryAB水平 将减少或阻断CP引起的心肌收缩功能缺陷。这些研究将在AIM I进行 -确定CP/CPB诱导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是否会减少心脏停搏液诱导的收缩 分离的心肌细胞的缺陷。目的III-确定特定的心脏收缩信号机制 与缺血诱导的SHSP蛋白改变有关。实验干预(药理学 和遗传方法)将使用分离的大鼠心肌细胞和朗宁多夫灌流 红心。 如果这些目的是成功的，这些研究将加强我们对CP诱导的收缩的理解 并提出治疗策略，可以极大地改善目前的心肌保护和 减少心脏手术相关并发症

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