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Ischemia-induced remodeling of the heart : macro- and micro-systems approach to heart function

缺血引起的心脏重塑：心脏功能的宏观和微观系统方法

基本信息

批准号：
12480256
负责人：
KAWAHARA Koichi
金额：
$ 10.5万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Cardiac ischemia results in the increased vulnerability to lethal arrhythmias such as ventricular tachycardia and fibrillation. Cardiac ischemia also produces the death of cardiac myocytes by either necrosis or apoptosis. The present study aims at elucidating the mechanisms responsible for remodeling in the post-infarcted heart, and for conversion between ventricular tachycardia(VT) and fibrillation(VF). The results are summarized as follows :1. Ligation of the left coronary artery of rat hearts resulted in the acute death of ventricular cardiac myocytes. Post-infarction left ventricular remodeling occurred at 2-3 weeks after the coronary artery ligation. TUNEL staining or immunohistochemical analysis using an anti-activated caspase-3 antibody revealed that apoptotic death of myocytes was observed almost coinciding with the morphological changes of the heart, suggesting that apoptosis of cardiac myocytes contributed to the process of post-infarction left ventricular remodeling.2. In Langendorff-perfused rat hearts, treatment with either L-NMMA, an inhibitor of nitric oxide synthase (NOS), or 5-HD, a specific blocker of mitochondrial ATP-sensitive potassium (mitoK__<ATP>) channels, during reperfusion attenuated the vulnerability to ischemia/reperfusion-induced VT/VF, suggesting that the increased production of nitric oxide (NO) and the resultant activation of mitoK__<ATP> channels during reperfusion were involved in the increased vulnerability to ischemia/reperfusion-induced VT/VF.3. In Langendorff-perfused rat hearts, perfusion with either ruthenium red (RR) or Ru 360, blockers of calcium uptake by mitochondria, resulted in the reversible conversion of VF to VT. Perfusion with spermine, an activator of mitochondrial calcium uptake, produced reversible conversion of VT to VF. These results suggested that changes in the calcium uptake by mitochondria contributed to the macro-dynamical transition between VT and VF.

心脏缺血导致更容易发生致命性心律失常，例如室性心动过速和颤动。心脏缺血还会导致心肌细胞通过坏死或凋亡而死亡。本研究旨在阐明梗死后心脏重塑以及室性心动过速（VT）和颤动（VF）之间转换的机制。研究结果如下： 1．结扎大鼠心脏左冠状动脉导致心室心肌细胞急性死亡。梗死后左心室重构发生在冠状动脉结扎后2-3周。 TUNEL染色或抗活化caspase-3抗体免疫组化分析显示，心肌细胞凋亡几乎与心脏形态变化同时发生，提示心肌细胞凋亡参与了梗死后左心室重构过程。 2．在 Langendorff 灌注的大鼠心脏中，再灌注期间用一氧化氮合酶 (NOS) 抑制剂 L-NMMA 或线粒体 ATP 敏感钾 (mitoK__<ATP>) 通道的特异性阻断剂 5-HD 进行治疗，可减弱缺血/再灌注引起的 VT/VF 的脆弱性，表明硝酸盐产生增加氧化 (NO) 和再灌注期间由此产生的 mitoK__<ATP> 通道的激活与缺血/再灌注引起的 VT/VF 的脆弱性增加有关。3。在 Langendorff 灌注的大鼠心脏中，灌注钌红 (RR) 或 Ru 360（线粒体钙摄取阻滞剂）导致 VF 可逆转化为 VT。精胺（线粒体钙吸收的激活剂）灌注可实现 VT 向 VF 的可逆转化。这些结果表明线粒体钙吸收的变化有助于 VT 和 VF 之间的宏观动力学转变。