Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets
Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets
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DOI：
10.1038/sj.gt.3301104
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发表时间：
2000-03-01
期刊：
影响因子：
5.1
通讯作者：
Ogihara, T
中科院分区：
文献类型：
--
作者：
Aoki, M;Morishita, R;Ogihara, T
使用血管生成生长因子来加速和/或增强侧支动脉发育的新治疗策略的可行性最近已进入缺血性疾病的治疗领域。肝细胞生长因子（HGF）是一种新的内皮细胞特异性生长因子，具有很强的促内皮细胞有丝分裂活性。虽然已经证明HGF在体外培养系统中是一种潜在的血管生成生长因子，但没有直接的体内证据表明HGF在生理条件下具有血管生成活性。在这项研究中，我们假设HGF基因转染到梗死心肌可以诱导血管生成，可能导致对缺氧的有益反应。用HVJ-脂质体法将SR α启动子驱动的人HGF基因或对照载体转染大鼠心肌。体内转染人HGF基因4d后，人HGF免疫反应阳性细胞数较对照组明显增加（P < 0.01）。在转染HGF载体的心肌中，观察到PCNA阳性内皮细胞显着增加，而在对照载体转染和未处理的心肌中检测到很少的PCNA阳性内皮细胞。与对照载体或赋形剂相比，HGF注射部位周围的血管数量显著增加（P < 0.01）。HGF载体转染诱导的血管生成活性也通过激活对血管生成至关重要的转录因子ets来证实。此外，我们研究了HGF在心肌梗死模型中的病理生理作用。心肌梗死后内源性肝细胞生长因子浓度明显降低。因此，我们推测，肝细胞生长因子基因转染到梗死心肌可以诱导一个有益的反应，减少内源性肝细胞生长因子。事实上，将人HGF转染到梗死心肌中也导致血管数量显着增加（P < 0.01），并伴有ets结合活性的显着诱导和血流量的显着增加。总之，本研究结果提供了直接的体内证据，通过转染人HGF基因在大鼠非梗死和梗死心肌中诱导血管生成。由转基因产生的局部HGF的持续产生可被认为是缺血性疾病如心肌梗死的创新治疗血管生成策略。
The feasibility of a novel therapeutic strategy using angiogenic growth factors to expedite and/or augment collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors whose mitogenic activity on endothelial cells is very potent. Although it has been demonstrated that HGF is a potential angiogenic growth factor in in vitro culture systems, there is no direct in vivo evidence for the angiogenic activity of HGF in physiological conditions. In this study, we hypothesized that transfection of HGF gene into infarcted myocardium could induce angiogenesis, potentially resulting in a beneficial response to hypoxia. Human HGF gene or control vector driven by the SR alpha promoter was transfected into rat myocardium by the HVJ-liposome method. Four days after in vivo transfection of human HGF gene, there was a marked increase in human immunoreactive HGF as compared with control vector (P < 0.01). In myocardium transfected with HGF vector a significant increase in PCNA-positive endothelial cells was observed while few PCNA-positive endothelial cells were detected in both control-vector-transfected and untreated myocardium. The number of vessels around the HGF injection sites was significantly increased as compared with control Vector or vehicle (P < 0.01). Angiogenic activity induced by the transfection of HGF vector was also confirmed by the activation of a transcription factor, ets, which is essential for angiogenesis. Furthermore, we studied the pathophysiological role of HGF in a myocardial infarction model. The concentration of endogenous HGF was significantly decreased in infarcted myocardium. Therefore, we hypothesized that transfection of HGF gene into infarcted myocardium could induce a beneficial response to the decreased endogenous HGF. indeed, transfection of human HGF into infarcted myocardium also resulted in a significant increase in the number of vessels (P < 0.01), accompanied by marked induction of ets binding activity and a significant increase in blood flow. Overall, the present results provide direct in vivo evidence for the induction of angiogenesis by transfection of the human HGF gene in rat non-infarcted and infarcted myocardium. The constant production of local HGF resulting from the transgene may be considered as an innovative therapeutic angiogenesis strategy for ischemic diseases such as myocardial infarction.