Chen Xue-Hai, Minatoguchi Shinya, Kosai Kenichiro, Yuge Kentaro, Takahashi Tomoyuki, Arai Masazumi, Wang Ningyuan, Misao Yu, Lu Chuanjiang, Onogi Hirohito, Kobayashi Hiroyuki, Yasuda Shinji, Ezaki Masayasu, Ushikoshi Hiroaki, Takemura Genzou, Fujiwara Takako, Fujiwara Hisayoshi
Department of Cardiology, Regeneration and Advanced Medical Science, Gifu University, Gifu, Japan.
J Card Fail. 2007 Dec;13(10):874-83. doi: 10.1016/j.cardfail.2007.07.004.
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.
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 14 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.
HGF gene therapy may be a novel therapeutic strategy against unstable angina pectoris or severe angina pectoris, which may progress to acute myocardial infarction.
据报道，肝细胞生长因子（HGF）可保护心脏免受缺血再灌注损伤。然而，缺血前体内腺病毒介导的HGF基因转移是否对缺血再灌注具有保护作用及其确切机制仍不清楚。
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具有心脏保护作用，如血管生成、Bcl-2过表达以及减少羟自由基、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面积。HGF基因转移后，兔经历30分钟冠状动脉闭塞以及30分钟、4小时、48小时和14天的再灌注。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小时时梗死面积显著减小（13.4%±2.3%）。再灌注14天时，HGF基因转移改善了左心室射血分数和缩短分数，减少了纤维化面积，并增加了危险区域的毛细血管密度。再灌注4小时时，与LacZ组和生理盐水组相比，HGF组危险区域Bcl-2蛋白过表达，TUNEL阳性心肌细胞的发生率显著降低。LacZ组和生理盐水组在缺血30分钟和再灌注30分钟期间，作为羟自由基指标的心肌间质2,5-二羟基苯甲酸水平升高，而HGF组受到显著抑制。
HGF基因治疗可能是针对不稳定型心绞痛或可能进展为急性心肌梗死的严重心绞痛的一种新型治疗策略。
