Modification of gap junctions during myocardial ischemia and its significance in myocardial necrosis

心肌缺血过程中间隙连接的修饰及其在心肌坏死中的意义

• 批准号: 13670731
• 负责人: MIURA Tetsuji
• 金额: $ 2.24万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670731/
• 关键词: myocardial ischemia; gap junction; connexin; protein kinase C

In the present study, we assessed 1) relationship between alteration of gap junction (GJ) permeability and myocardial necrosis during ischemia and 2) effects of ischemic preconditioning (PC) on connexin43 (Cx43) and GJ function. Significant dephosphorylation was detected after 30 min of ischemia, and this dephosphorylation was suppressed by inhibition of protein kinase C (PKC) in a rabbit model of myocardial ischemia. PC induced translocation of PKC-ε to the intercalated disk and significantly accelerated this ischemia-induced Cx43 dephosphorylation. Reduction in GJ permeability during myocardial ischemia was similarly accelerated by PC and a GJ blocker, heptanol. Three structurally different GJ blockers (heptanol, 2,3-butanedione monoxime, 18β-glycyrrhetinic acid) that were infused after the onset of ischemia limited infarct size after 30-min ischemia/2-h reperfusion, and their cardioprotective effects were equivalent to PC. These results suggest that GJ is a determinant of myocardial necrosis during ischemia/reperfusion and that PC accelerates GJ closure during ischemia possibly by PKC-mediated Cx43 dephosphorylation, leading to cardioprotection.

在本研究中，我们评估了 1) 缺血期间间隙连接 (GJ) 通透性改变与心肌坏死之间的关系，以及 2) 缺血预处理 (PC) 对连接蛋白 43 (Cx43) 和 GJ 功能的影响。缺血 30 分钟后检测到显着的去磷酸化，并且在兔心肌缺血模型中通过抑制蛋白激酶 C (PKC) 来抑制这种去磷酸化。 PC 诱导 PKC-ε 易位至闰盘，并显着加速缺血诱导的 Cx43 去磷酸化。 PC 和 GJ 阻滞剂庚醇同样会加速心肌缺血期间 GJ 通透性的降低。缺血发生后输注的三种结构不同的GJ阻滞剂（庚醇、2,3-丁二酮单肟、18β-甘草次酸）在30分钟缺血/2小时再灌注后限制了梗塞面积，其心脏保护作用与PC相当。这些结果表明，GJ 是缺血/再灌注期间心肌坏死的决定因素，并且 PC 可能通过 PKC 介导的 Cx43 去磷酸化加速缺血期间的 GJ 闭合，从而实现心脏保护。