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Development of Chronic Heart Failure Model Caused by Inflammatory Cytokines and Establishment of Prophylactic and Therapeutic Strategies for the Heart Failure

炎症细胞因子所致慢性心力衰竭模型的建立及心力衰竭防治策略的建立

基本信息

批准号：
08557050
负责人：
SHIMOKAWA Hiroaki
金额：
$ 4.48万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

(1)We have developed a canine model of sustained myocardial dysfunction, in which interleukin-1beta (lL-1beta) bound to microspeheres (MS) was selectively injected into the left main coronary artery. This novel model is unique as the long-term effect of an inflammatory cytokine on the heart can be examined without causing its systemic effect. In this model, sustained left ventricular (LV) dysfunction was noted in animals that received IL-1beta-MS but not in those that received MS alone.(2)First, the role of adhesion molecules was examined. When the adhesion molecule inhibitor, SLeX-oligosaccharide (SLeX-OS), or the P-selectin inhibitor, PB1.3, was pre-administered, the leukocyte infiltration and sustained LV dysfunction caused by IL-1beta were markedly inhibited, indicating the important role of adhesion molecules in this model.(3)Second, the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) was examined. When the non-specific protein synthase inhibitor, dexamethasone … More (DEX), or the iNOS inhibitor, aminoguanidine (AG), was pre-administered, the IL-beta-induced sustained myocardial dysfunction was markedly prevented, indicating the important role of iNOS-derived NO in the pathogenesis of the myocardial dysfunction in this model.(4)Third, the role of superoxide anion was examined. When the superoxide anion synthesis inhibitor, OPC-6535, was pre-administered, the IL-1beta-induced sustained myocardial dysfunction was markedly prevented, indicating that superoxide anion may also play an important role in our model.(5)Finally, we measured the myocardial concentrations of nitrotyrosine as a marker for peroxynitrite production as a result of the interaction between NO and superoxide anion. Superoxide anion is known to be a more cytotoxic factor than NO or superoxide anion. The results showed that nitrotyrosine formation was increased in the IL-beta group, whereas the formation was markedly inhibited in the SLeX-OS, PB 1.3, DEX, AG, and OPC-6535 groups. There was a significant correlation between he myocardial concentrations of nitrotyrosine and LV dysfunction, indicating that peroxynitrite is at least one of the major causative factors for the myocardial dysfunction in our model in vivo. Less

(1)We已经开发了一种持续心肌功能障碍的犬模型，其中将与微球（MS）结合的白细胞介素-1 β（IL-1 β）选择性地注射到左主冠状动脉中。这种新的模型是独特的，因为可以检查炎性细胞因子对心脏的长期影响，而不会引起其全身效应。在该模型中，在接受IL-1 β-MS的动物中观察到持续的左心室（LV）功能障碍，但在仅接受MS的动物中未观察到。（2）首先，研究粘附分子的作用。当预先给予粘附分子抑制剂SLeX-寡糖（SLeX-OS）或P-选择素抑制剂PB1.3时，由IL-1 β引起的白细胞浸润和持续的LV功能障碍被显著抑制，表明粘附分子在该模型中的重要作用。（3）诱导型一氧化氮合酶（inducible NO synthase，iNOS）所产生的一氧化氮（nitric oxide，NO）的作用。当非特异性蛋白合成酶抑制剂地塞米松 ...更多信息 (DEX)或预先给予iNOS抑制剂氨基胍（AG），可明显预防IL-β诱导的持续性心肌功能障碍，提示iNOS源性NO在该模型心肌功能障碍的发病机制中起重要作用。（4）研究了超氧阴离子的作用。当预先给予超氧阴离子合成抑制剂OPC-6535时，IL-1 β诱导的持续性心肌功能不全被显著预防，表明超氧阴离子在我们的模型中也可能发挥重要作用。（5）最后，我们测定了心肌中硝基酪氨酸的浓度，作为NO与超氧阴离子相互作用产生过氧亚硝酸盐的标志物。超氧阴离子是一种比NO或超氧阴离子更具细胞毒性的因子。结果显示，IL-β组中硝基酪氨酸形成增加，而SLeX-OS、PB 1.3、DEX、AG和OPC-6535组中硝基酪氨酸形成显著抑制。心肌硝基酪氨酸浓度与左室功能障碍之间存在显著相关性，表明过氧亚硝酸盐至少是我们体内模型中心肌功能障碍的主要致病因素之一。少