In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions
In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions
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DOI：
10.1016/j.cardfail.2007.07.004
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发表时间：
2007-12-01
影响因子：
6
通讯作者：
Fujiwara, Hisayoshi
中科院分区：
文献类型：
--
作者：
Chen, Xue-Hai;Minatoguchi, Shinya;Fujiwara, Hisayoshi
背景：肝细胞生长因子（HGF）对缺血再灌注损伤具有保护作用。然而，腺病毒介导的肝细胞生长因子基因在缺血前的体内转移是否对缺血再灌注具有保护作用及其确切机制尚不清楚。方法和结果：通过使用兔缺血再灌注损伤模型，我们证明HGF基因转移通过其多种有益作用，如血管生成，Bcl-2过表达，减少羟基自由基，脱氧尿苷-5 '-三磷酸生物素缺口末端标记（TUNEL）阳性心肌细胞和纤维化区域，具有心脏保护作用。HGF基因转染后，兔冠状动脉闭塞30分钟，再灌注30分钟，4小时，48小时和1.4天。与LacZ组（36.5% ± 2.0%）和生理盐水组（40.3% ± 3.2%）相比，HGF组再灌注48小时的梗死面积显著减少（13.4% ± 2.3%）。在再灌注14天，HGF基因转移改善左心室射血分数和缩短分数，减少纤维化面积，并增加危险区的毛细血管密度。再灌注4小时，Bcl-2蛋白过度表达，HGF组危险区TUNEL阳性心肌细胞的发生率显著低于LacZ组和生理盐水组。心肌间质2，5-二羟基苯甲酸水平，羟基自由基的指标，增加在缺血30分钟和再灌注30分钟的LacZ和生理盐水组，并显着抑制HGF组。结论：HGF基因治疗可能成为治疗不稳定型心绞痛或严重心绞痛的一种新的治疗策略。
Background: Hepatocyte growth factor (HGF) is reported to protect the heart against ischemia-reperfusion injury. However, whether in vivo adenovirus-mediated HGF gene transfer before ischemia is protective against ischemia-reperfusion and its precise mechanisms are still unknown. Methods and Results: By using a rabbit model of ischemia-reperfusion injury, we demonstrate that HGF gene transfer is cardioprotective through its multiple beneficial actions, such as angiogenesis, Bcl-2 overexpression, and decreasing hydroxyl radicals, deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL)-positive myocytes, and fibrotic area. After HGF gene transfer, the rabbits underwent 30 minutes of coronary occlusion and 30 minutes, 4 hours, 48 hours, and 1.4 days of reperfusion. The infarct size at 48 hours of reperfusion was significantly reduced in the HGF group (13.4% +/- 2.3%) compared with that in the LacZ group (36.5% +/- 2.0%) and saline group (40.3% +/- 3.2%). At 14 days of reperfusion, HGF gene transfer improved left ventricular ejection fraction and fractional shortening, reduced the fibrotic area, and increased the capillary density in the risk area. At 4 hours of reperfusion, Bcl-2 protein was overexpressed and the incidence of TUNEL-positive myocytes was significantly decreased in the risk area in the HGF group compared with the LacZ and saline groups. The myocardial interstitial 2,5-dihydroxybenzoic acid level, an indicator of hydroxyl radical, increased during 30 minutes of ischemia and 30 minutes of reperfusion in the LacZ and saline groups, and was significantly inhibited in the HGF group. Conclusion: HGF gene therapy may be a novel therapeutic strategy against unstable angina pectoris or severe angina pectoris, which may progress to acute myocardial infarction.