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Plasma soluble Fas, an inhibitor of apoptosis, definitely improves long-term prognosis of patients with chronic heart failure

血浆可溶性 Fas，一种细胞凋亡抑制剂，确实可以改善慢性心力衰竭患者的长期预后

基本信息

批准号：
11670669
负责人：
NISHIGAKI Kazuhiko
金额：
$ 2.24万
依托单位：
GIFU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670669/
关键词：
intraabdominal administration of soluble Fas plasma soluble Fas apoptosis 心不全予後

项目摘要

This study was aimed to clarify the molecular biophsiological mechanisms of heart failure, and to clarify whether plasma sFas, an inhibitor of apoptosis, can improve the long-term prognosis of rat with old myocardial infarction, as a model of heart failure.Experiments were performed on 30 6-wk-old male rat for suffering from heart failure caused by myocardial infarction, and the same number of rat for producing Sham operation, as a control. In 1999, we successfully performed to make a model of heart failure after acute myocardial infarction made by ligation of proximal site of left coronary artery.In 2000, we measured the plasma sFas concentration in 12 weeks heart failure rat model after the myocardial infarction. As a result, plasma sFas was clarified to elevate in heart failure. In addition, in the cardiac muscle tissue of the rat, we recognized TUNEL positive myocytes which suggested existence of DNA fragmentation, as a marker of apoptosis, and upregulation of Fas and Bax, apoptosi … More s inducers. In findings of electron microscope of cardiac muscle tissue, hypertrophy and degeneration of myocytes and deformity of myocytic nucleus were observed. However, specific condensation of chromatin, shrinkage, budding, and apoptotic body of myocytes, which suggested apoptosis, was not observed.We clarifled the findings of fibrosis in myocytes, which suggested myocyte cell death by optical microscope. In addition, the frequency of the myocytes showing TUNEL positive was equal to or less than 1%. Accordingly, the absence of apoptosis findings with electron microscope did not mean that there was not apoptosis in myocytes, but observation area by electron microscope was too small.Subsequently, we performed to administrate sFas into the above heart failure rats via intraabdominal injection. However, we did not reach plasma sFas level to produce elevation of persistence of significance, and was not able to confirm improvement of heart failure. Because, turnover of plasma sFas is considered earlier unexpectedly in intraabdominal administration of sFas. Therefore, intraabdominal administration of sFas was not accepted for sFas expression extend over a long period of time. We concluded that gene therapy of sFas is necessary to realize continuous expression in myocardial tissue. Less

本研究旨在阐明心力衰竭的分子生物生理机制，并阐明血浆sFas作为一种凋亡抑制剂是否可以改善老年性心肌梗死大鼠的长期预后，作为心力衰竭模型。实验以30只6周龄心肌梗死心力衰竭雄性大鼠和30只相同数量的假手术雄性大鼠作为对照。1999年，我们成功地用左冠状动脉近端结扎法制作了急性心肌梗死后心力衰竭模型。2000年，我们测量了心肌梗死后12周心力衰竭大鼠模型的血浆sFas浓度。结果表明，血浆sFas在心力衰竭时升高。此外，在大鼠心肌组织中，我们发现了TUNEL阳性的肌细胞，这表明存在DNA片段，作为细胞凋亡的标志，凋亡诱导剂Fas和Bax上调。电镜观察心肌组织肌细胞肥大变性，肌细胞核畸形。然而，没有观察到肌细胞染色质凝结、收缩、出芽和凋亡小体等提示细胞凋亡的现象。我们在光学显微镜下阐明了心肌细胞纤维化的发现，提示心肌细胞死亡。此外，TUNEL阳性的肌细胞的频率等于或小于1%。因此，电镜下未见凋亡并不意味着肌细胞没有凋亡，而是电镜下观察面积太小。随后，我们对上述心力衰竭大鼠进行腹腔注射给药。然而，我们没有达到血浆sFas水平产生持续性显著性升高，也不能证实心力衰竭的改善。因为，在腹腔内给药时，血浆sFas的周转被出乎意料地提前考虑。因此，对于长时间持续表达的sFas，腹腔内给药是不被接受的。我们认为，sFas基因治疗是实现心肌组织持续表达的必要条件。少