Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation
Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation
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DOI：
10.1136/hrt.2008.152223
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发表时间：
2009-02-01
期刊：
影响因子：
5.7
通讯作者：
Nagaya, N.
中科院分区：
文献类型：
--
作者：
Yamahara, K.;Min, K. D.;Nagaya, N.
目的：最近，一项临床试验开始评估自体骨髓间充质干细胞（MSC）经血管内移植治疗心力衰竭（HF）的疗效。由于一些HF患者衍生的血清不诱导自体MSC增殖，本研究的目的是阐明体液因子在血清中减弱MSC激活，并探讨这些体液因子在HF的发病机制中的作用。方法和结果：通过培养人MSC与10个HF患者（FS 100 pg/ml）和4个健康对照组的血清中存在的抑制作用进行分析。在这些患者中，两种来自HF患者的血清对MSC增殖显示出显著的抑制活性。蛋白质芯片和ELISA分析显示，这些血清含有高水平的血管抑素以及基质金属蛋白酶（MMP）-9，它产生血管抑素的活性形式。Angiostatin可显著抑制人MSC的增殖和迁移，并呈剂量依赖性地增加其凋亡。在大鼠心力衰竭模型中，血清血管抑制素和基质金属蛋白酶水平升高，但用基质金属蛋白酶抑制剂治疗可抑制这些升高。结论：结果表明，血管抑制素可以减弱MSC的活性，可能在心力衰竭的进展中发挥作用。
Objective: Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.Methods and results: Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS 100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.Conclusions: The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF.