Myofibril damage during low-flow ischemia

低流量缺血期间的肌原纤维损伤

• 批准号: 6542045
• 负责人: ROBERT S DECKER
• 金额: $ 42.15万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542045
• 关键词: binding proteins; cardiac myocytes; chemical aggregate; cytoprotection; cytoskeletal proteins; cytoskeleton; dogs; heart circulation; heart contraction; heat shock proteins; microfilaments; myocardial ischemia /hypoxia; myofibrils; myosins; phosphorylation; sarcomeres

DESCRIPTION (provided by applicant): The reversible contractile dysfunction that follows episodes of low-flow ischemia is believed to represent an adaptive response to reduced coronary flow and/or transient myocardial injury. Conceptually, when flow and function are matched at some reduced level, the heart is thought to have adapted to preserve myocardial viability. If contractile function remains depressed despite the restoration of normal coronary flow, then flow and function become mismatched and the myocardium is said to be stunned. Studies in the chronically instrumented canine heart demonstrate that viable cardiac myocytes disclose areas of disrupted myofibrils when flow and function remain mismatched. Myofibril anomalies that appear following low-flow ischemia include the development of thick filament disorder within the sarcomere and myofibrillar thick filament disruption. These structural alterations are accompanied by changes in the phosphorylation of myosin binding protein-C (MyBP-C). Since MyBP-C is believed to regulate thick filament structure and function, changes in the phosphorylated state of MyBP-C may be instrumental in initiating thick filament disorder, disruption and contractile dysfunction. Other cytoskeletal elements are altered as well, including the formation of actin aggregates, disruption of intermediate filaments and depolymerization of microtubules. Small heat shock proteins, HSP27 and aB-crystallin, interact with actin and desmin, respectively, and HSC7O forms high molecular weight aggregates with tubulin. Experiments outlined in this proposal are designed to answer the following questions: (1) does dephosphorylation of MyBP-C induce contractile dysfunction; (2) does dephosphorylation of MyBP-C initiate thick filament disorder and disruption; and (3) does redistribution of small heat shock proteins and HSC7O protect myofibrillar and cytoskeletal proteins? Identifying the mechanism(s) that alter myofibril structure following low-flow ischemia may make it possible to control flow-function matching, preserve cardiocyte viability and minimize myocardial injury from repeated ischemic episodes.

描述(申请人提供)：低流量缺血发作后出现的可逆性收缩功能障碍被认为是对冠脉流量减少和/或一过性心肌损伤的适应性反应。从概念上讲，当血流和功能在某个降低的水平上匹配时，心脏被认为已经适应了保持心肌存活的能力。如果尽管冠状动脉血流恢复正常，但收缩功能仍然受到抑制，那么血流和功能就会变得不匹配，心肌就会被认为是顿抑。在长期仪器化的犬心脏上的研究表明，当血流和功能保持不匹配时，存活的心肌细胞会暴露出被破坏的肌原纤维区域。低流量缺血后出现的肌原纤维异常包括肌节内粗丝紊乱和肌原纤维粗丝断裂。伴随着这些结构变化的是肌球蛋白结合蛋白C(MyBP-C)的磷酸化变化。由于MyBP-C被认为调节粗丝的结构和功能，MyBP-C的磷酸化状态的变化可能有助于启动粗丝的紊乱、断裂和收缩功能障碍。其他细胞骨架元素也会改变，包括肌动蛋白聚集体的形成，中间丝的破坏和微管的解聚。小分子热休克蛋白HSP27和AB-晶状体蛋白分别与肌动蛋白和结蛋白相互作用，HSC7O与微管蛋白形成高分子量聚集体。本提案中概述的实验旨在回答以下问题：(1)MyBP-C的去磷酸化是否会导致收缩功能障碍；(2)MyBP-C的去磷酸化是否会引发粗丝紊乱和断裂；以及(3)小分子热休克蛋白和HSC7O的重新分布是否会保护肌纤维和细胞骨架蛋白？确定低流量缺血后改变肌原纤维结构的机制(S)可能使控制血流-功能匹配、保存心肌细胞活力和将反复缺血发作对心肌的损伤降至最低。