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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.

心脏缺血导致对致命性心律失常的易感性增加，如室性心动过速和纤颤。心肌缺血也会导致心肌细胞的死亡，要么是坏死，要么是凋亡。本研究旨在阐明梗死后心脏重构以及室性心动过速(VT)和纤颤(VF)之间转换的机制。主要结果如下：1.结扎大鼠左冠状动脉可致心肌细胞急性死亡。冠脉结扎后2~3周出现心肌梗死后左室重构。结果：1.TUNEL染色或抗caspase-3抗体免疫组织化学分析显示，心肌细胞的凋亡性死亡与心脏的形态变化基本一致，提示心肌细胞的凋亡参与了心肌梗死后左室重构的过程。在朗宁多夫灌流的大鼠心脏上，一氧化氮合酶抑制剂L-NMMA或线粒体三磷酸腺苷敏感钾通道的特异性阻断剂5-HD在再灌流期间可降低对缺血/再灌注性室速/室颤的易感性，提示再灌流期间一氧化氮(NO)的产生增加以及由此引起的线粒体三磷酸腺苷通道的激活参与了对缺血/再灌注性室速/室颤易感性的增加。在朗宁多夫灌流的大鼠心脏上，用Ru红(RR)或Ru 360(线粒体钙摄取的阻断剂)灌流，可导致VF向VT的可逆转换。用线粒体钙摄取激活剂精胺灌流，可使室性心动过速逆转为室性心动过速。这些结果提示，线粒体钙摄取的改变参与了VT和VF之间的宏观动力学转换。