Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1
Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1
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DOI：
10.1016/j.yjmcc.2008.04.011
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发表时间：
2008-07-01
影响因子：
5
通讯作者：
Chau, Lee-Young
中科院分区：
文献类型：
--
作者：
Lin, Heng-Huei;Chen, Yen-Hui;Chau, Lee-Young
血红素氧合酶-1（HO-1）是一种应激诱导酶，在心血管系统中具有多种保护功能。研究表明，在缺血性梗死（MI）急性期心肌HO-1的适时过表达通过其抗凋亡和抗炎作用提供保护。在这里，我们证明了延迟HO-1转导介导的重组腺相关病毒在缺血性心脏的小鼠永久性冠状动脉结扎显着减弱左心室纤维化和心脏功能障碍后4周MI检查。HO-1介导的保护作用与缺血心肌血管化增强相关。HO-1基因转移导致在结扎后10天招募到梗死区域的c-kit（+）-干细胞数量显著增加。HO-1介导的干细胞募集也在接受静脉输注携带绿色荧光蛋白的骨髓干细胞的非缺血小鼠的心脏中得到证实。进一步的实验显示，血管内皮生长因子（VEGF）和基质细胞衍生因子-1（SDF-1）在HO-1转导的心肌中高度诱导。单核细胞浸润明显，并与血管生成因子共定位于同一区域。从HO-1转导的左心室分离的单核细胞的流式细胞术分析显示，超过50%的细胞表达CD 34，造血干细胞和内皮祖细胞的标志物。中和抗体阻断VEGF和SDF-1可显著减弱HO-1介导的梗死小鼠的新生血管形成和保护作用。这些数据表明，心肌梗死后心脏HO-1基因转移至少部分通过诱导血管生成因子和募集循环祖细胞/干细胞促进新血管形成来提供保护。(C)2008年爱思唯尔公司All rights reserved.
Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with multiple protective functions in cardiovascular systems. Studies have shown that the timely cardiac HO-I overexpression at acute phase of ischemic infarction (MI) provides protection via its anti-apoptotic and anti-inflammatory effects. Here we demonstrate that a delayed HO-1 transduction mediated by a recombinant adeno-associated virus in ischemic hearts of mice with permanent coronary artery ligation significantly attenuated left ventricular fibrosis and cardiac dysfunctions examined at 4 weeks post MI. HO-1-mediated protection was correlated with enhanced vascularization in the ischemic myocardium. HO-1 gene transfer resulted in a notable increase in the number of c-kit(+)-stem cells recruited to the infarcted area at 10 days after ligation. HO-1-mediated stem cell recruitment was also demonstrated in the heart of non-ischemic mice receiving intravenous infusion of green fluorescent protein-bearing bone marrow stem cells. Additional experiments revealed that vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were highly induced in HO-1-transduced myocardium. Mononuclear cell infiltration was evident and colocalized with angiogenic factors in the same region. Flow cytometry analysis of the mononuclear cells isolated from HO-1-transduced left ventricles revealed that over 50% of cells expressed CD34, a marker of hematopoietic stem cells and endothelial progenitor cells. VEGF and SDF-1 blockade by neutralizing antibodies significantly attenuated HO-1-mediated neovascularization and protection in infarcted mice. These data suggest that cardiac HO-1 gene transfer post MI provides protection at least in part by promoting neovascularization through inducing angiogenic factors and the recruitment of circulating progenitor/stem cells. (C) 2008 Elsevier Inc. All rights reserved.