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New therapy against myocardial infarction using synthetic peptides

使用合成肽治疗心肌梗塞的新疗法

基本信息

批准号：
02557038
负责人：
YAZAKI Yoshio
金额：
$ 6.91万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02557038/
关键词：
RGD Acute Myocardial Infarction Myocardial Reperfusion Injury Cell Adhesion Molecules Antibody treatment CD11a, b, c 心筋虚血再潅流 DD11a,b,c CD54(ICAM-1)CD62(GMP-140)CD11a,b,c CD54(ICAMー1)CD18

项目摘要

The migration of neutrophils into tissues is the central event in myocardial hypoxiareoxygenation (H/R) as well as in inflammatory responses. The rolling of neutrophils has been revealed to be the first step of the interaction of the neutrophils with the vessel wall during an inflammatory response, which is dependent of the expression of granule membrane protein-140 (GMP-140) on the surface of vascular endothelial cells. First, using an in vitro model of H/R,we showed that higher number of neutrophils adhered to human umbilical vein endothelial cells (HUVECs) subjected to 60 minutes of hypoxia followed by 30 minutes of reoxygenation compared with neutrophils adhered to HUVECs subjected to no stimulation of I/R,and that preincubation of HUVECs with anti-human GMP-140 antibody blocked these adhesion. Furthermore, immunoperoxidase staining clarified, for the first time, that H/R enhanced the expression of GMP-140 on the surface of HUVECs. Next, using an in vivo rat model of myocardial ischemiareperfusion (I/R), we indicated that within 2 hours after reperfusion leukocytes began to infiltrate into the rat myocardia subjected to 30 minutes of ischemia, and clarified, for the first time, that the expression of intercellular adhesion molecule-1 (ICAM-1) was enhanced on the capillary and venous endothelial cells from 8 to 96 hours after the start of reperfusion. Furthermore, pretreatment with individual monoclonal antibodies against cell-adhesion molecules (CD11a, CD11b+c, CD18 and ICAM-1) reduced not only the infiltration of leukocytes but also the area of infarction in the reperfused hearts. Our present study suggests that the expression of GMP-140 along with ICAM-1 on vascular endothelial cells play a critical role in myocardial injury induced by I/R.

中性粒细胞向组织的迁移是心肌缺氧氧合（H/R）和炎症反应的中心事件。在炎症反应中，中性粒细胞的滚动是中性粒细胞与血管壁相互作用的第一步，这依赖于血管内皮细胞表面颗粒膜蛋白140 （GMP-140）的表达。首先，通过体外H/R模型，我们发现缺氧60分钟后再氧合30分钟的人脐静脉内皮细胞（HUVECs）粘附的中性粒细胞数量高于未进行I/R刺激的人脐静脉内皮细胞粘附的中性粒细胞数量，并且用抗人GMP-140抗体对HUVECs进行预孵育可阻断这些粘附。此外，免疫过氧化物酶染色首次证实H/R增强了huvec表面GMP-140的表达。接下来，我们利用大鼠心肌缺血再灌注（I/R）模型，发现缺血30分钟的大鼠心肌在再灌注后2小时内白细胞开始向心肌浸润，并首次明确了在再灌注开始后8 ~ 96小时毛细血管内皮细胞上细胞间粘附分子-1 （ICAM-1）的表达增强。此外，使用抗细胞粘附分子（CD11a、CD11b+c、CD18和ICAM-1）的单克隆抗体预处理，不仅可以减少白细胞的浸润，还可以减少再灌注心脏的梗死面积。我们目前的研究表明GMP-140和ICAM-1在血管内皮细胞上的表达在I/R诱导的心肌损伤中起关键作用。