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Important role of Placental Growth Factor on the healing process after acute myocardial infarction

胎盘生长因子对急性心肌梗死后愈合过程的重要作用

基本信息

批准号：
17590761
负责人：
UEMURA Shiro
金额：
$ 2.24万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590761/
关键词：
Myocardial Infarction Regeneration Medicine Placental Growth Factor 再生医療

项目摘要

Background : Recent studied indicates that therapeutic angiogenesis with vascular endothelial cell growth factor-A (VEGF-A) is not always effective in acute myocardial infarction (MI), mainly because it induces only immature vasculature. Placental growth factor (P1GF), a member of VEGF family, is different from VEGF-A in receptor specificity. P1GF specifically binds to VEGF receptor-1 (flt-1), though VEGF-A binds to both VEGF receptors 1 and 2. Recent our clinical work demonstrates that P1GF is rapidly produced within infarct myocardial tissue, and the plasma level of P1GF is positively correlated with number of monocytes and CD34 positive cells, and improvement of left ventricular function. However, therapeutic effects of P1GF on MI are not understood.Methods and Results : One day before ligation of coronary artery, recombinant human P1GF (rhP1GF) (10μg) was infused into the peritoneal cavity of C57BL/6 mice through subcutaneously implanted osmotic mini pump until 2 days after the lig … More ation. After 28 days, survival rate was significantly higher in rhP1GF-treated Group (70.0%) than PBS-Group (33.3%) (p<0.05). Seven days after MI, the infarct area, stained by 1.5% TTC (2,3,5-triphenyltetrazolium chloride), was smaller in rhP1GF-treated group (4.25±2.04mm^2) than PBS-group (5.95±1.54mm^2), and it indicates exogenous P1GF suppressed cardiac remodeling. Echocardiography also revealed that left ventricular diastolic diameter was decreased (rhP1GF: 4.50±0.46mm, PBS: 5.14±0.38mm p<0.01), and ejection fraction was increased in rhP1GF-treated group (rhP1GF: 40.6±9.17%, PBS: 25.7±7.23% p<0.01). Histological analysis showed that both CD31-positive vascular endothelial cells (rhP1GF: 644.6±90.54/mm^2, PBS: 459.0±73.89/mm^2 p<0.01) and a-smooth muscle actin-positive vessels (rhP1GF: 31.6±7.20/mm^2, PBS: 23.5±7.41/mm^2 p<0.01) was increased at infarct area, and it implied that both angiogenesis and arteriogenesis contributes to the improvement of cardiac function.Conclusion : rhP1GF-treatment preserved left ventricular function and inhibited post-infarct remodeling by enhancing neovascularization and arteriogenesis, through which rhP1GF-treatment improved survival rate after myocardial infarction. Less

背景：最近的研究表明，血管内皮细胞生长因子- a （VEGF-A）治疗性血管生成在急性心肌梗死（MI）中并不总是有效，主要是因为它只诱导未成熟的血管。胎盘生长因子（P1GF）是VEGF家族的一员，其受体特异性与VEGF- a不同。P1GF特异性结合VEGF受体-1 (flt-1)，而VEGF- a同时结合VEGF受体1和2。近年来我们的临床工作表明，P1GF在梗死心肌组织内迅速产生，血浆P1GF水平与单核细胞和CD34阳性细胞数量及左心室功能改善呈正相关。然而，P1GF对心肌梗死的治疗作用尚不清楚。方法与结果：冠状动脉结扎前1天，通过皮下植入渗透性微型泵将重组人P1GF (rhP1GF) （10μg）注入C57BL/6小鼠腹腔，直至结扎后2 d。28 d后，rhp1gf治疗组的成活率（70.0%）显著高于pbs治疗组（33.3%）（p<0.05）。心肌梗死后7 d， 1.5% TTC（2,3,5-三苯四唑氯）染色显示，rhp1gf治疗组心肌梗死面积（4.25±2.04mm^2）小于pbs治疗组（5.95±1.54mm^2），提示外源性P1GF抑制心肌重构。超声心动图显示，rhP1GF治疗组左室舒张直径减小（rhP1GF: 4.50±0.46mm, PBS: 5.14±0.38mm p<0.01），射血分数升高（rhP1GF: 40.6±9.17%,PBS: 25.7±7.23% p<0.01）。组织学分析显示，梗死区cd31阳性血管内皮细胞（rhP1GF: 644.6±90.54/mm^2, PBS: 459.0±73.89/mm^2 p<0.01）和a-平滑肌肌动蛋白阳性血管（rhP1GF: 31.6±7.20/mm^2, PBS: 23.5±7.41/mm^2 p<0.01）均增加，提示血管生成和动脉生成均有助于心功能的改善。结论：rhp1gf通过增强心肌梗死后新生血管和动脉生成，保护左心室功能，抑制梗死后重构，提高心肌梗死后存活率。少